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Clinical practice guidelines for the management of adult gliomas

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Clinical Practice Guidelines
for the management of adult
gliomas: astrocytomas and
oligodendrogliomas
August 2009
В© Cancer Council Australia/Australian Cancer Network/Clinical Oncological Society of Australia
Inc. 2009
ISBN: 978-0-9775060-8-8
This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may
be reproduced by any process without prior written permission from the Cancer Council
Australia/Australian Cancer Network/Clinical Oncological Society of Australia Inc. Requests and
enquiries concerning reproduction and rights should be addressed to the Copyright Officer, Cancer
Council Australia, GPO Box 4708, Sydney NSW 2001, Australia. Website: <www.cancer.org.au>
Email: [email protected]
Conflict of interest
The development of these clinical practice guidelines has been undertaken by a non-remunerated
Working Party of the Australian Cancer Network, with the assistance of a generous private donation.
Some members of the Working Party have received sponsorship to attend scientific meetings, been
supported in the conducting of clinical trials or have been involved in an advisory capacity by
pharmaceutical and biochemical companies.
The Australian Cancer Network holds a register of conflict of interest.
Acknowledgement
This draft document Clinical Practice Guidelines for the management of adult gliomas: astrocytomas
and oligodendrogliomas has been produced by the Australian Cancer Network from the generous
donation received from Mr Steven Newton in memory of his late wife Valerie Newton, together with
funding from the Cancer Council Australia.
Disclaimer
This document is a general guide to appropriate practice, to be followed only subject to the clinicians’
judgement in each individual case.
The recommendations are designed to provide information to assist decision-making and are based on
the best information available at the date of compilation. The guide is not meant to be prescriptive.
Suggested citation:
Australian Cancer Network Adult Brain Tumour Guidelines Working Party. Clinical Practice
Guidelines for the Management of Adult Gliomas: Astrocytomas and Oligodendrogliomas. Cancer
Council Australia, Australian Cancer Network and Clinical Oncological Society of Australia Inc.,
Sydney 2009.
CONTENTS
Preface ………………. .........................................................................................................................iv
Foreword
......................................................................................................................................v
Summary of recommendations and key points .................................................................................... vii
INTRODUCTION
Chapter 1
Setting the scene ...........................................................................................................1
APPROACH TO PATIENT
Chapter 2
Approach to patient.....................................................................................................10
Chapter 3
Clinical trials and research..........................................................................................21
DIAGNOSIS
Chapter 4
Clinical presentation ...................................................................................................30
Chapter 5
Imaging .......................................................................................................................41
Chapter 6
Diagnosis and pathology.............................................................................................66
TREATMENT
Chapter 7
Low-grade astrocytomas.............................................................................................73
Chapter 8
High-grade astrocytomas ............................................................................................88
Chapter 9
Oligodendrogliomas..................................................................................................134
Chapter 10
Complementary, alternative and unproven therapy ..................................................145
CONTINUING CARE
Chapter 11
Symptom management and complications ...............................................................152
Chapter 12
Psychosocial care ......................................................................................................173
Chapter 13
Rehabilitation............................................................................................................191
Chapter 14
Follow-up..................................................................................................................198
END-OF-LIFE CARE
Chapter 15
Palliative care............................................................................................................211
APPENDICES
Appendix 1
Working party membership and contributors to guidelines......................................235
Appendix 2
Glossary and abbreviations .......................................................................................239
Appendix 3
Guidelines development process...............................................................................243
Index
……………………………………………………………………………...............246
Contents
iii
PREFACE
This publication will be of great value to the brain tumour patient, their family and caregivers in
Australia because it will set out the type of treatment that a patient should receive, taking into account
their tumour and individual health situation.
It provides a documented benchmark which the interested health care consumer can consult to check
whether their treatment accords with what is regarded as standard therapy in the developed world. Let
us not forget that many, if not most, of the 200,000 people who are diagnosed worldwide each year
with a malignant primary brain tumour are unlikely to have access to even the minimum standard of
care outlined in these pages.
On the other hand, significant sections of these Guidelines should be out of date as soon as they are
published. That might sound odd but that is the only way we will advance towards a cure for these
highly lethal tumours - ideally, new therapies and approaches will be discovered rapidly as we march
towards a "cure" and not just palliation.
Hope has been generated by the choice of gliomas as one of the priority areas for attention under the
human genome project and the unprecedented number of clinical trials for brain tumours, either from
a company initiative or from an independent researcher. What has been discovered already is pointing
towards a new era of combination and targeted therapies.
The journey with a brain tumour is not one that anyone undertakes in a voluntary capacity. It is
enormously challenging, for the patient, their family and caregiver. One hopes that the information
contained in these Guidelines will help to make that journey just a little easier.
On behalf of brain tumour consumers we offer our thanks to those who were involved with the
drafting of this document and those who undertook the basic research in the hundreds of learned
papers that provide the evidence base for its conclusions.
Denis Strangman
Consumer Representative
Brain Tumour Guidelines Working Party
Chair and Co-Director
International Brain Tumour Alliance IBTA
iv
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
FOREWORD
Brain tumours are uncommon tumours but they have a devastating effect on patients’ lives and the
lives of their caregivers. Although malignant brain tumours make up only two percent of all cancers
they result in the fourth highest loss of potential years of life.1 On average a patient with a malignant
brain tumour loses 12 years of potential life; the highest average loss of life from any type of cancer.
Because of this, brain tumours cause the highest economic burden on Australian cancer patients’
households, with an average cost estimated to be more than five times higher than for breast or
prostate cancer patients.2
These guidelines have been developed to provide information on malignant adult brain tumours
(specifically gliomas) to medical practitioners and interested community members. The aim is to
direct attention to improve the level of practice and understanding in a health area that causes
considerable community anxiety. Brain tumours also contribute heavily through costs of hospital,
home and community management to the budget of the Australian health care system. They impose
the highest economic burden on carers of any cancer, as well as significant emotional and physical
challenges.
Guidelines for adult gliomas are needed because of the considerable variation in clinical practice. A
patterns-of-care study in Victoria3 has recently documented that only 74% of patients were referred
for radiotherapy and only 54% saw a medical oncologist. Radiotherapy offers a major survival benefit
but only 68% of patients with glioblastoma multiforme received radiotherapy. It is unlikely that onethird of patients were too unfit for treatment. There is no reason to believe that the situation is
different in other Australian States.
It is a common misconception that there is not much evidence to support glioma management. This is
far from the case; high-level randomised data exist from many trials of treatment and for many
supportive interventions. Controversies exist and are best viewed in the light of systematically
assembled evidence. Thus the necessary conditions exist for the development of guidelines; a high
community burden, evidence of variation in practice and good evidence on optimum patient
management.
These guidelines are for the management of adult gliomas including low- and high-grade gliomas
(anaplastic astrocytoma, glioblastoma multiforme and oligodendroglioma). They encompass all
aspects of patient management, not just treatment. A general approach to patients is suggested
because it is recognised that a diagnosis of brain tumour can have profound implications. Clinical
presentation, diagnostic work up and imaging are reviewed. Treatment is discussed separately for
low-grade gliomas, high-grade gliomas and oligodendrogliomas.
Clinical trials are the major route for the development of new treatments, yet in the Victorian study3,
only 5% of patients participated in clinical trials. We present a chapter on clinical trials as a resource
to encourage greater participation in trials.
A great many cancer patients seek further hope in complementary, alternative and unproven
treatments. We provide some guidance on the range of treatments offered and some tools for the
critical appraisal of complementary, alternative and unproven treatments.
We also present guidance about continuing care including psycho-social support, the management of
symptoms, rehabilitation, follow-up and palliative care. Management is often complex because of the
interaction of multiple medical problems and behavioural and psychosocial issues. We examine in
detail the management of headaches, steroids and anti-convulsants and the current legal requirements
about driving.
Foreword
v
As with all of the Australian guidelines, these guidelines were produced by a group of experts who
have donated their time and have spent many laborious hours reviewing the medical literature and
conferring with their colleagues. We are especially grateful to Ms Christine Vuletich at the Australian
Cancer Network for her unstinting efforts to collate and produce the finished guidelines document. As
with all national cancer guidelines, the adult glioma guidelines have benefited greatly from the
guidance, wisdom, persistence and energy of Emeritus Professor Tom Reeve who has steered the
executive group through the very long process of guidelines development. These guidelines would not
have been possible without them and the generous donation of Mr Steven Newton in memory of his
wife Valerie. A consumer version and guidance for general practitioners will be prepared to follow
these guidelines. We intend to publish these guidelines on-line as a wiki to facilitate wider
dissemination and the rapid incorporation of new evidence.
References
1
Australian Institute of Health and Welfare and Australasian Association of Cancer Registries.
Cancer in Australia 2001. Canberra: AIHW; 2004.
2
Access Economics. Cost of cancer in NSW. Sydney: Cancer Council NSW; 2006 Jun 15.
3
Rosenthal MA, Drummond KJ, Dally M, Murphy M, Cher L, Ashley D et al. Management of
glioma in Victoria (1998–2000): retrospective cohort study. Med J Aust 2006; March
20;184(6):270–3.
Professor Michael Barton OAM
Chair, Brain Tumour Guidelines Working Party
Professor of Radiation Oncology, UNSW
Liverpool Cancer Therapy Centre
Locked Bag 7103
Liverpool BC NSW 1871
Email: [email protected]
Dr Elizabeth Hovey
Project Officer, Brain Tumour Guidelines Working Party
Senior Staff Specialist
Department of Medical Oncology
Prince of Wales Hospital
Level 2, High Street
Randwick NSW 2031
Email: [email protected]
vi
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
SUMMARY OF RECOMMENDATIONS AND KEY POINTS
(Levels of evidence and references shown for Recommendations only)
Level of
evidence
Key points and recommendations
Refs
1. Setting the scene
•
Astrocytomas and oligodendrogliomas are the largest groups of
gliomas, which are primary CNS cancers.
•
Primary CNS cancers are diagnosed in 7/100,000 Australians each
year, compared with colon cancer 60/100,000 per year.
•
Although uncommon, CNS cancers are associated with the highest
potential years of life lost of all major cancers–on average 12 years
per patient.
•
Most astrocytomas and oligodendrogliomas occur in the brain, with
only 5% in the spinal cord. They have a tendency to progress to
more malignant grades over time.
•
Gliomas are more common in males. Median age at diagnosis is
55-59 years in males, 60-64 years in females.
•
Incidence has increased slightly over the last twenty years,
probably due to improved imaging and more investigation in
elderly patients.
•
Incidence of glioma does not vary much between geographical
areas.
•
Median survival after resection is five to eight years for low-grade
astrocytoma, three years for patients with anaplastic astrocytoma,
about one year for patients with GBM, up to ten years for lowgrade oligodendroglioma and one to seven years for anaplastic
oligodendroglioma. Younger age, good preoperative
performance status and gross macroscopic resection are
associated with longer survival.
•
Nearly all CNS cancers arise randomly. The only known cause is
ionising radiation.
•
Known risk factors for developing glioma are increased age, male
sex and rare familial genetic syndromes.
•
Except possibly for neurofibromatosis type 1, no screening test is
available for glioma as early detection does not increase the
benefit of treatment.
2. Approach to the patient
•
The approach to the patient must include recognition of the
concerns of family members and caregivers and incorporate
attention to complex medical and psychosocial issues.
Summary of recommendations and key points
vii
Key points and recommendations
•
Cognitive deficits are common with gliomas and can impair
patients' abilities to comprehend information and specifically their
capacity to provide informed consent for treatment. In the area of
shared decision making, the guiding principles should be to respect
patients’ autonomy and to act in the patients’ best interests.
•
Good practice points:
-
Present information in a clear and unambiguous way. Avoid
medical jargon and use lay terms where possible.
-
Encourage the patient to ask questions about any aspects of
the treatment/s.
-
Elicit the patients’ values and preferences.
-
Negotiate a treatment decision with the patient.
-
Where possible, include another person in the room during
your consultation with the patient (essential if there is any
degree of cognitive impairment).
-
Where possible, aim to discuss while the person is still
competent to make decisions the sort of treatment and care
they would like to receive if their illness progressed.
-
Ask the person to nominate a surrogate-decision maker
should their condition deteriorate and encourage the patient
to discuss their wishes about treatment with this person.
Level of
evidence
3. Clinical trials and research
•
Eligible patients should be offered clinical trial participation or
referred to a centre where clinical trial participation is available.
•
The ethical principles of written informed consent should be
carefully considered in patients with cognitive impairment,
receptive dysphasia, or impairment of judgment.
•
Multidisciplinary involvement in a trial management committee is
recommended for clinical trials in gliomas.
•
The use of several corroborative endpoints such as six-month
progression-free survival, radiological response, cognitive function,
and health-related quality of life are recommended for clinical trials
in gliomas, however overall survival is the most robust endpoint.
•
Validated tools should be used for measurement of neurocognitive
function and health-related quality of life.
•
Clinical trials in glioma should include central review of
histopathology and radiological endpoints.
•
Consideration should be given to collection of tissue for biobanking
and at autopsy in clinical trials.
viii
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Refs
Key points and recommendations
Level of
evidence
Refs
Time to progression is a better surrogate for survival than objective
radiological response and should be incorporated as an endpoint in
clinical trials.
III
23
Patients in clinical trials should be stratified for known important
prognostic factors.
III
9
Central specialised neuro-pathology review must be incorporated into
therapeutic clinical trials in brain tumours.
II
14
Validated health-related quality of life (HRQL) tools are available and
should be used where measurement of HRQL is planned.
III
25,26
4. Clinical presentation
A patient with new onset or recurrent headache uncharacteristic for
that patient should also be imaged, particularly if there are focal
neurological symptoms and signs.
•
Patients presenting with a first seizure should have adequate neuroimaging with MRI.
•
All patients who present with focal neurological symptoms (such as
hemiparesis, dysphasia, dysarthria, neglect, hemianopia, dressing
apraxia) require neuro-imaging to establish the cause of these
symptoms.
•
Consider referral of patients with glioma to a clinical genetics
service if the patient or their first- or second-degree relatives have
features or family history suggestive of neurofibromatosis type 1 or
tuberous sclerosis.
•
Consider referral of patients with high-grade gliomas to a Cancer
Genetics Service/Familial Cancer Clinic if there is a personal or
family history (first or second-degree relatives) of premenopausal
breast cancer, sarcoma, acute leukaemia or paediatric cancer,
especially where two or more of these other cancer types have
occurred and where one or more cases have occurred before age
45.
•
Consider referral of patients with high-grade gliomas to a Cancer
Genetics Service/Familial Cancer Clinic if there is a personal or
family history (first- or second-degree relatives) of bowel, uterine,
stomach, ovarian, biliary/pancreatic or small intestinal cancer or
TCC of the upper ureter, especially where two or more cases of
these other cancers have occurred, and/or where one or more of
these have been diagnosed before age 50.
III
11,13,
14,17
Summary of recommendations and key points
ix
Key points and recommendations
Level of
evidence
5. Imaging
•
Neuro-imaging is an essential component of glial series tumour
management.
•
CT and MRI form the mainstay of tumour imaging.
•
The main aims of imaging of brain tumours are to:
-
primarily diagnose or refine a suspected diagnosis
-
optimally localise the lesion
-
characterise the lesion
-
assess the lesion’s secondary effects and complications
-
plan surgical and radiation treatment including the provision
of input data for neuronavigation
-
quantify therapeutic response
-
recognise post-treatment progression and complications
•
CT (with or without the use of intravenous contrast) because of its
ready availability is most often the first examination to reveal the
possibility of an intracranial neoplasm.
•
CT also helps also with the assessment of calcified and
haemorrhagic lesions as well as those that may involve bone.
•
CT requires the use of x-rays (ionising radiation).
•
Contrast-enhanced MRI is the imaging modality of choice for the
diagnostic workup of an intracranial lesion because of its superior
soft tissue resolution and multi-planar imaging capabilities.
•
MRI has a greater accuracy in lesion depiction compared with CT.
•
MRI is contraindicated in patients with ferromagnetic aneurysm
clips, cardiac pacemakers, cochlear implants and intra-orbital
metallic foreign bodies.
x
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Refs
Key points and recommendations
Level of
evidence
•
No combination of clinical symptoms and signs reliably differentiate
brain tumours from benign causes.
•
MRI and CT cannot reliably predict tumour type; biopsy and
histological assessment are required.
•
Standardised tumour imaging protocols are necessary.
•
The timing of imaging must be appropriate to the patient’s clinical
state.
•
Scanning should be supervised by an accredited MRI and/or
neuro-radiologist.
•
Ideally, all scans performed outside of the neurosciences centre
should be reviewed by the neuro-radiological team prior to
treatment.
•
Gliomas, particularly high-grade lesions, are heterogeneous
structurally and are disseminated at the time of diagnosis.
•
Contrast-enhancing portions may either over- or under-estimate the
presence of active tumour.
•
Low-grade glioma (LGG) will grow slowly in size, with a significant
proportion undergoing anaplastic progression.
•
Glial tumours can have imaging characteristics that allow diagnosis
and an estimation of pathological grade, however there is
significant overlap and inconsistencies that limit accuracy of
diagnosis. Biopsy is therefore required.
•
The appearances of brain stem and optic pathway gliomas may
be very typical and given the risks of biopsy, treatment is often
commenced on the basis of imaging appearances alone.
•
Reporting of neuro-oncology should ideally be performed by
neuro-radiologists.
•
The radiological report is a dynamic phenomenon and may
change with additional clinical or ancillary information.
•
More structured and standardised reporting is recommended.
•
If there are features that warrant emergency management, this
should be directly conveyed to the referring physician as soon as
possible.
•
It is important to assess and document tumour response to
treatment.
Refs
Summary of recommendations and key points
xi
Key points and recommendations
•
�Neuronavigation’ projects CT and/or MRI data into the operative
field for better anatomical orientation, better defining of
anatomical landmarks, better positioning of the craniotomy flap,
and precise targeting of pathological structures and tumour
margins during operative procedures.
•
Intra-operative MRI can compensate for brain shifts and therefore
allows a better assessment of the extent of resection.
•
Reactive post-operative changes can be seen as early as 18 hours
on MRI and can last for years.
•
Immediate post-operative imaging may help to differentiate
between residual tumour, postoperative reactive changes and
parenchymal damage as a result of treatment.
•
Contrast-enhanced MRI is more sensitive in detecting changes
compared with CT, however it still has limitations, notably with highgrade non-enhancing lesions.
•
Adherence to standardised imaging protocols is advised to aid in
the interpretation of subsequent follow-up studies.
xii
Level of
evidence
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Refs
Key points and recommendations
Level of
evidence
•
The aim of follow-up imaging is to monitor for treatment response,
tumour recurrence or progression and to assess for any possible
treatment-related side effects.
•
No adequate data exist on the role of imaging in the monitoring of
response to therapy of gliomas, but nevertheless, this forms a
significant part of neuro-oncology imaging.
•
MRI is the best imaging modality for the follow-up of glial series
tumours, however the optimal frequency of these studies is
unknown. Based on neuro-oncology trials, apart from any
immediate post-operative scan the first baseline examination is
usually performed between six weeks and three months after the
completion of definitive treatment, then at two to three month
intervals. If the disease is found to be stable, the interval may be
increased to six months.
•
The difficulty in distinguishing between changes that may indicate
a response to treatment and those indicating progressive tumour
growth are important limitations of follow-up imaging.
•
Follow-up neuro-oncology imaging protocols should be
standardised.
•
A description of the lesion on follow-up studies should include an
objective measurement of tumour size.
•
Radiation necrosis is an uncommon irreversible progressive necrotic
mass which is often identical in appearance to that of progressive
residual or recurrent HGG and exists more often in combination with
residual tumour. No adequate data are available on the role of
imaging in differentiating between tumour recurrence and therapyrelated changes.
•
Forms of advanced MRI that have been applied to neurooncology include MR spectroscopy (MRS), diffusion imaging,
perfusion imaging and fMRI.
•
Patho-physiological changes are the focus of these techniques in
disease.
•
There is no high-level evidence indicating better outcomes or
management cost --effectiveness when using these techniques.
Refs
Summary of recommendations and key points
xiii
Key points and recommendations
•
With the availability of CT and MRI, the use of nuclear imaging
studies for brain tumours is no longer routine.
•
The use of scintigraphy is limited to research protocols and some
specific clinical indications in centres with appropriate expertise.
•
Thallium (201Tl) is the most frequently used isotope in neuro-SPECT,
and may be helpful in pre-operative grading of the lesion and
differentiating between recurrent high-grade glioma and radiationinduced necrosis.
•
Fluorodeoxyglucose (18F FDG) is the most commonly used isotope in
neuro-PET. This may have a role in pre-operative grading,
evaluating the extent of tumour infiltration, finding an appropriate
site for biopsy, and detecting malignant transformation in lowgrade lesions.
Level of
evidence
6. Diagnosis and pathology
•
The histological diagnosis of brain tumours should be undertaken by
a neuro-pathologist or by an appropriately trained anatomical
pathologist with some experience in tumour neuropathology.
•
Ideally all tissue removed from the patient should be submitted for
pathological examination, including aspirated material and the
material from ultrasonic surgical aspirators.
•
A pathology report should include at least the following
information: demographic and clinical data; a macroscopic
description of the material received; a microscopic description; a
diagnosis incorporating tumour type (astrocytic, oligodendroglial)
and tumour grade; and identification of any prognostic and/or
predictive factors.
•
A histological diagnosis should take precedence over tissue
banking when the specimen is small.
7. Low-grade astrocytomas
•
Definitive diagnosis cannot be made on imaging alone. The
presence or absence of enhancement offers some guidance but is
not absolutely specific. Non-enhancing tumours may be high
grade. Enhancing tumours may be low grade.
•
If the patient has been informed of all the pros and cons of a
conservative approach and elects to wait then this is reasonable.
This option is especially applicable if the tumour is less than 10cm3 in
volume, diffuse on T2 MRI scan and in an eloquent area.
•
Once progression has been documented treatment should be
offered before the onset of fixed neurological deficits.
xiv
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Refs
Key points and recommendations
Level of
evidence
Refs
A tissue diagnosis should be obtained in all patients with a suspected
high-grade astrocytoma before commencing definitive treatment.
III
115
Anti-neoplastic treatment should not be offered without a tissue
diagnosis unless biopsy is considered too dangerous.
III
90-100
Patients with high-grade astrocytoma should have surgery for tumour
resection if safe as this extends survival when compared to biopsy
alone.
II
125,126
Patients with high-grade astrocytoma should have surgery for maximal
tumour resection, aiming for gross macroscopic resection if safe, as this
extends survival when compared to biopsy, subtotal or partial
resection.
II
127
•
Histological diagnosis may be unreliable because of sampling error.
•
Pre-operative MR imaging may have a closer correlation with
survival than histological grading on biopsy.
•
There is definitely a role for attempted resection of a low grade
astrocytoma (LGA). It should probably be done at the time of
diagnosis for the following potential benefits: more accurate
diagnosis, palliation of symptoms, extension of survival, reduced
chance of malignant transformation and possible cure.
•
Recommendation of resection should be tempered if the tumour is
diffuse, located in an eloquent area or less than 10cm3 in volume.
•
Standard microsurgical techniques should be employed with the
addition of stereotactic guidance if available.
•
Awake surgery or cortical mapping are optional but may reduce
the incidence of post-operative neurological deficit if the aim of
surgery is to palliate and secure a diagnosis rather than prolong life
or achieve a cure.
•
When no other treatment can be offered and there is clear clinical
and/or radiological progression, there is definitely a role for
radiotherapy. In the post-surgical setting, its role is less well defined.
If surgery offers relief of symptoms and halts progression, then
adjuvant treatment can be reserved for progressive disease. If
radiotherapy is given immediately after surgery, it will extend time to
progression (TTP) but will not extend OS any longer than if given
later when the disease progresses. The role of chemotherapy in the
treatment of LGAs is unclear.
8. High-grade astrocytomas
Summary of recommendations and key points
xv
Key points and recommendations
Level of
evidence
Refs
Patients with high-grade astrocytoma who are over the age of 65 or
have poor performance status should have surgery for tumour
resection if they are fit for surgery, as this extends survival when
compared to biopsy alone.
II
126
Patients with high-grade astrocytoma benefit from implantation of
carmustine wafers at the time of surgical resection of tumour as they
provide a modest survival benefit of 8 to 11 weeks.
I
139-141
Patients with recurrent high-grade astrocytoma, particularly younger,
asymptomatic patients, may benefit from resection of tumour.
III
156,161166,168
Surgery for patients with high-grade astrocytomas should be
conducted in accredited facilities complying with all relevant State,
Federal, professional and educational policies, standards and
guidelines.
III
156,161166,168
Surgery for patients with high-grade astrocytomas should be
conducted in a multidisciplinary environment with input from
neuroradiology, intensive care, medical and radiation oncology,
neuropathology, neurology, specialist surgery and nursing and allied
health services.
III
156,161166,168
Surgery for patients with high-grade astrocytomas should be
conducted in a facility where an operating microscope, ultrasonic
surgical aspirator and cortical mapping equipment are available.
III
156,161166,168
Intra-operative frameless neuronavigation improves extent of resection
and survival of patients with high-grade astrocytoma compared to
unguided microsurgery, and its use is recommended.
III
178,180
Patients with high-grade astrocytoma should have radiotherapy
because this extends median survival times when compared to no
radiotherapy.
I
5,6,194,
195,198
Radiotherapy should start as soon as possible after a diagnosis of highgrade astrocytoma is established.
II
202, 203
The standard radiotherapy dose and fractionation schedule for
patients with high-grade astrocytoma is 60Gy in 2Gy fractions and
there is no evidence that higher doses improve outcome.
I
206-208
For adjuvant radiotherapy for high-grade astrocytoma, conventional
fractionation (single daily fractions of 2Gy) is recommended. There is no
evidence that hyperfractionation and/or accelerated fractionation
improves outcome.
I
218, 219
Focal dose escalation with brachytherapy or stereotactic radiosurgery
as part of initial radiotherapy for patients with high-grade astrocytoma
does not improve outcome.
I
230
xvi
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points and recommendations
Level of
evidence
Refs
There is insufficient evidence to recommend short-course radiotherapy.
II
104
For patients with high-grade astrocytoma, post-operative radiotherapy
fields should include the tumour bed with a margin rather than the
whole brain.
II
246,247
For radiotherapy for high-grade astrocytoma, involved field
radiotherapy provides equivalent rates of local control and recurrence
patterns to whole-brain radiotherapy.
III
230,251253,263
The treatment volume or planning target volume (PTV) is defined as:
III
255
Both CT and MRI should be used for target volume delineation.
III
256,262
Histopathology remains the gold standard for diagnosis of radiation
necrosis.
III
271
Adjuvant chemotherapy after surgery and radiotherapy provides
modest improvement in progression free survival and overall survival for
patients with GBM.
I
275
II
7
Adjuvant chemotherapy after surgery and radiotherapy improves
disease free survival and is recommended for patients with anaplastic
astrocytoma (AA).
I
271
Concurrent radiotherapy and chemotherapy followed by adjuvant
chemotherapy provides a significant improvement in median and twoyear survival in patients with GBM and is recommended.
II
7
•
Short-course low-dose radiotherapy may be suitable for
patients with poor performance status who are keen to have
treatment.
-
clinical target volume (CTV) + 5mm
-
CTV = Gross tumour volume (GTV) + high-signal area on T2weighted MRI or perifocal hypodense zone on CT
-
GTV = contrast-enhancing area on CT or T1-weighted MRI
However, adjuvant chemotherapy alone has been supplanted by
concurrent chemo-radiotherapy followed by adjuvant chemotherapy
and is thus not currently recommended.
•
There are no data regarding either safety or efficacy of concurrent
radiotherapy and chemotherapy followed by chemotherapy in
patients with anaplastic astrocytoma and the regimen is not
recommended.
7
Summary of recommendations and key points
xvii
Key points and recommendations
•
Level of
evidence
7
There are no data regarding concurrent radiotherapy and
chemotherapy followed by chemotherapy in patients with ECOG
performance status 3 or 4 and glioblastoma multiforme or
anaplastic astrocytoma and the regimen is not recommended.
277
As there are insufficient data to make a recommendation for
management with concurrent adjuvant radiotherapy and
chemotherapy followed by chemotherapy in patients over 70 with
glioblastoma multiforme or anaplastic astrocytoma, treatment
decisions should be made on an individual basis.
Postoperative adjuvant temozolomide without radiotherapy is safe and
tolerable in patients over age 70 with good performance status.
Comparison of outcome with other regimens has not been made.
Treatment decisions should be made on a case-by-case basis.
•
Refs
III
278
277
There are no data regarding chemotherapy without radiotherapy
for patients with high-grade astrocytoma and poor performance
status and chemotherapy alone is not recommended as an
alternative to radiotherapy.
III
290-292
All patients with suspected oligodendroglioma (OG) or
oligoastrocytoma (OA) should undergo a biopsy for histological
confirmation of tumour type and grade and to permit molecular
analysis.
III
13,14
Maximal gross surgical resection is recommended where technically
feasible, as this has been shown to increase survival.
IV
10,12
All suspected OGs / OAs must undergo histological confirmation as
radiological features alone are inadequate for diagnosis and staging.
V
9,13
Observation only may be an acceptable strategy in grade II tumours
with good prognostic features.
V
15
External beam radiotherapy is a standard treatment for OG and OA.
II
19, 20
Chemotherapy has modest activity in recurrent high-grade
astrocytoma. A decision on its use should be made after discussion of
risks and benefits, and consideration of other therapeutic options, but is
generally recommended.
•
The optimal duration of temozolomide treatment in patients with
recurrent high-grade astrocytoma is not yet defined.
9. Oligodendrogliomas
•
1p/19q testing should be performed on all tumours with
oligodendroglial features.
xviii
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points and recommendations
Level of
evidence
Refs
The recommended radiotherapy dose is 50Gy in 2Gy fractions over six
weeks.
II
19
Radiotherapy fraction size should not exceed 2Gy per day for high dose treatments.
II
22–26
II
1, 31
•
Response to temozolomide chemotherapy correlates with 1p-/19q-.
Adjuvant PCV chemotherapy is not recommended for high-grade OG
and OA as standard therapy because there is no improvement in
overall survival.
•
Chemotherapy-naive patients with high-grade oligodendroglioma
who have recurred following radiotherapy will often respond to
chemotherapy.
•
For recurrent high-grade OG, there may be a role for further
chemotherapy and consideration of re-irradiation in patients with
good performance status.
10. Complementary, alternative and unproven therapy
•
There is no unifying definition of CAM and treatment that may fall
within the definition of �complementary’, such as counselling, has
high-level evidence to support its use.
•
There is evidence for an increasing interest in and use of CAM.
•
Antineoplastic activity of CAM in malignant glioma is supported by
low-level evidence only, such as case reports, and cannot be
recommended.
•
There needs to be a distinction between quality-of-life benefits and
antineoplastic activity when assessing potential benefit.
•
Quality of life and/or symptom management such as control of
nausea and vomiting with acupuncture are supported by good
evidence.
•
Some of the modalities that may fall within the definition of CAM
(eg counselling) are part of mainstream clinical practice and
supported by high-level evidence.
Summary of recommendations and key points
xix
Key points and recommendations
Level of
evidence
Refs
Prophylactic anticonvulsants are not recommended. However, once
started, an anticonvulsant is best withdrawn over several weeks.
I
1,6
Anticonvulsant treatment should be commenced after the first seizure
in patients with gliomas.
II
14,15
If a decision to discontinue anticonvulsants is made, the drug should be
withdrawn slowly, over two to three months.
I
1
Treatment with dexamethasone is recommended in patients who are
symptomatic and have cerebral oedema. The usual starting dose is
16mg per day.
III
26
The dose of dexamethasone should be gradually tapered to
the lowest amount that controls the patient’s symptoms.
Dexamethasone should not be discontinued abruptly.
III
26,28
Blood glucose concentrations, upper and lower limb power and weight
should be assessed prior to starting corticosteroids and at regular
intervals after treatment is started.
III
2
Treatment with a proton pump inhibitor is recommended if a patient
receiving corticosteroids is also being treated with a NSAID or an
anticoagulant, or if the patient has a past history of peptic ulcer
disease.
I
2,26
Treatment with a proton pump inhibitor should be considered in
patients receiving dexamethasone in a dose exceeding 16mg per day,
or 16mg per day for a long interval.
I
2,26
•
There are potentially very important toxicities associated with CAM
caused by interactions with conventional medicines and primary
toxicity.
•
Many patients do not discuss CAM usage with their medical
practitioner.
•
For malignant glioma there is no high-level evidence for
antineoplastic activity of CAM.
•
Clinicians should enquire about the use of CAM in a nonconfronting and non-judgemental way.
•
Health professionals should not participate in the administration of
unproven anti-cancer treatments.
11. Symptom management and complications
xx
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points and recommendations
Level of
evidence
Refs
Prophylactic treatment for osteoporosis should be started in postmenopausal women receiving corticosteroids and in pre-menopausal
women and men if the T score is less than -1.5. The Australian
Pharmaceutical Benefits Scheme currently approves the use of
risedronate in patients on steroids for greater than three months with a T
score of less than -1.
I
30
Cutaneous drug eruptions with onset after 10 days of exposure to the
drug, if associated with mucosal involvement or with systemic features,
may be serious and require changing the antiepileptic medication to
another group or category of drugs.
III
14
Either a nuclear scintigraphic ventilation-perfusion (V/Q) or a CT
pulmonary angiogram can be used to diagnose pulmonary embolus. A
�low-probability’ V/Q scan does not absolutely exclude the possibility of
a pulmonary embolus.
I
47
The D-dimer, together with a careful clinical assessment, may be used
to exclude a VTE and avoid unnecessary other investigations.
II
47
Perioperative thromboprophylaxis with a LMWH is recommended for
most patients with gliomas, although subcutaneous UFH is a reasonable
alternative unless there is evidence of haemorrhage.
I
61
Prophylaxis is particularly appropriate for patients with high-grade
gliomas and in elderly and immobile patients.
I
41
Thromboprophylaxis should be interrupted for surgery (no LMWH for at
least 24 hours prior to surgery), resumed during the post-operative
period, and continue until the patient is fully mobile. Mechanical
measures to avoid VTE are recommended as adjunctive therapy.
III
48,49
Anticoagulation with LMWH alone or followed by warfarinisation (for a
period depending on the clinical scenario) is recommended as
therapy for VTE in patients with gliomas. Exceptions may include
anticoagulation in the immediate post-operative period, in which case
a temporary IVC filter should be considered.
II
68
IV
14,15,
•
When a new rash occurs in patients on anticonvulsants, liver and
renal function should be checked to assess internal organ toxicity.
12. Psychosocial care
Cognition dysfunction may not be apparent during brief consultations,
and debilitating deficits will often only be detected by formal
neuropsychological assessment undertaken by a trained health
professional.
17,19
Summary of recommendations and key points
xxi
Key points and recommendations
Level of
evidence
Refs
Health professionals should consider the need for formal
neuropsychological assessment to determine the nature of cognitive
deficits and provide a basis for recommendations regarding capacity
to return to previous roles, and to assist the patient and their family to
adjust.
IV
17
A medical practitioner must provide the patient with information to
allow the patient to make an informed decision about treatment. A
patient must be advised about the nature of their condition, any
alternative forms of treatment that may be available, the
consequences of those forms of treatment, and the consequences of
remaining untreated.
I
27
It is up to the treating practitioner to determine whether a patient is
competent to make a treatment decision.
I
27
Health professionals should determine the capacity of the patient to
make decisions, and be aware of legislation that applies in the case of
patients who are not competent to make decisions. Health
professionals should be prepared to review this capacity as it may
change over time.
I
27,29
Patients who have risk factors for increased psychological distress
should be offered referral for psychosocial treatment as this minimises
the likelihood that they will develop significant distress.
I
45
Identification of depression and anxiety is important as these disorders
can be effectively treated with a combination of supportive
psychotherapy, cognitive and behavioural techniques, and
pharmacotherapy.
I
49
When delirium is suspected, urgent identification and treatment of the
cause must take place while pharmacological and nonpharmacological treatments are initiated to reduce the distress of the
patient and their family.
IV
46
If organic mental disorder is suspected, the patient must be assessed for
treatable causes, and specialist psychiatric advice obtained about
management.
IV
46
•
•
•
xxii
Cognitive and personality changes are common and have a
powerful adverse impact on quality of life.
Delirium should be suspected in any patient who demonstrates an
abrupt change in behaviour, personality or mood.
The contribution of patient neuropsychiatric symptoms and
personality changes to carer distress may outweigh the burden
posed by physical symptoms. Patient personality changes can lead
to social isolation that compounds distress.
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points and recommendations
Level of
evidence
Refs
Patients and their families should be informed that in general, talking
about their feelings improves adjustment.
II
58
Patients and their carers should be asked about their emotional
adjustment and given information about available support groups and
specialist services, as these have been demonstrated to be effective in
reducing distress.
I
45,66,67
Brain tumour patients should receive neuro-rehabilitation and can
achieve functional gains and rates of discharge comparable to those
of patients with stroke with a shorter hospital stay.
III
5,7
Patients having residual problems after treatment of a glioma, with
stable medical status, should be referred to a rehabilitation service with
a range of medical, nursing and allied health professionals, for multidisciplinary assessment and appropriate therapy and support of their
problems, involving both the patient and their carers.
III
7-11,18
Physiotherapy should be offered to these glioma patients with residual
problems in motor function, strength, and coordination, or balance
and gait problems.
III
9,10,20
Occupational therapy should be offered to these glioma patients with
residual problems in personal care and independent activities of daily
living. As well as treating individual needs, therapy should also address
the person’s social and physical environment of care, and be
supported by social worker intervention.
III
10
Therapy by a speech pathologist should be offered to these glioma
patients with residual problems related to swallowing, communication
and cognitive function. Where the services are available, this should be
supported by assessment and intervention by a clinical psychologist, or
a neuropsychologist.
III
7
Glioma patients expecting to return to driving after treatment of their
tumour should be referred to a rehabilitation service for full assessment
of their ability to drive safely. Any resulting determinations of the driver
licensing authority must be observed. For those who can return to
driving, regular ongoing follow-up by the rehabilitation service is
indicated, to review and manage any on-going risk associated with
driving. Those who continue to drive unsafely, contrary to advice and
the determinations of the driver licensing authority, should be
counselled about the need to behave responsibly and the advice of
the authority be sought, if they still continue to drive. In some situations,
cancellation of the driver’s licence may be necessary.
I
19
13. Rehabilitation
14. Follow-up
Summary of recommendations and key points xxiii
Key points and recommendations
Level of
evidence
Refs
I
6,7,8
Methods used to identify survival time have limitations in accuracy and
precision and are therefore not routinely recommended for
determining the timing of referral to palliative care.
I
21,22
All patients with advanced progressive life-limiting disease should be
given the opportunity to discuss prognosis and end-of-life issues.
IV
33
Medications (corticosteroids, megestrol acetate) may be trialled as a
treatment of fatigue.
II
40,41
Psychostimulants are not recommended for fatigue, outside of clinical
trials.
II
42
Psychosocial interventions and energy conservation may help with
fatigue.
II
39
Opioids are the analgesics of choice for moderate to severe cancer
pain.
I
44
Artificial nutrition is not recommended in patients with advanced
cancer because it does not reduce morbidity or mortality.
I
51
Meticulous attention must be given to mouth care in the dying patient.
IV
53
IV
74
•
The aim of follow-up for patients is to evaluate tumour control,
monitor and manage symptoms from tumour and treatment and
provide psychological support.
•
The optimal frequency of follow-up visits is unknown and should be
determined by the patient’s clinical condition.
•
Follow-up should be undertaken in a setting where the patient has
access to members of the multi-disciplinary team.
•
Dexamethasone dose should be gradually reduced and ceased
when possible.
15. Palliative care
Specialist palliative care services can improve outcomes in the care of
patients with cancer and should be available for all appropriate
patients.
•
•
Referral to palliative care should not be limited to the end-of-life
phase of illness.
The issue of parenteral hydration in the dying patient remains
controversial.
Opioids applied topically (eg morphine paste or liquid) can relieve the
pain associated with pressure area wound care.
xxiv
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points and recommendations
•
Level of
evidence
Refs
III
94
IV
95
IV
99,100
Patients should be maintained on the lowest possible effective
steroid dose to minimise side-effects.
With regard to steroids, the clinician should;
•
Dose according to each patient’s individual needs.
•
Consider pulsed rather than continuous treatment.
•
Monitor continuously for side-effects.
•
If no longer of benefit, wean down slowly and discontinue.
•
Consider prophylactic nystatin and gastroprotection in all patients,
especially those with added risk factors.
All patients requesting euthanasia should be thoroughly assessed in
terms of their symptoms and mental wellbeing, in particular, assessing
them for evidence of depression. All symptoms should be managed,
including offering treatment and counselling for depression if present.
•
Early and ongoing advanced care planning is important and
health practitioners should initiate end of life conversations and
advanced care planning as early as appropriate.
Non-essential medications should be discontinued while essential
medications are prescribed by an appropriate route.
•
Pain is the most common and most feared symptom of advanced
disease and analgesics must always be continued.
Involvement of a community palliative care service makes it more likely
that the patient will die at home.
•
Risk factors for complicated grief include:
-
Male gender
-
Lack of coping mechanisms
-
History of mental illness
-
Multiple losses
-
Intense brief relationship with deceased
-
Lack of support and family cohesion
-
Unexpected or traumatic death
-
Financial difficulties
-
Summary of recommendations and key points
xxv
1
SETTING THE SCENE
1.1
Introduction
These guidelines cover the most common primary central nervous system (CNS) cancers or malignant
tumours known as gliomas, which include astrocytoma, glioblastoma multiforme (GBM) and
oligodendroglioma (Table 1.1). The guidelines do not cover secondary (metastatic) cancers that have
spread to the brain from primary cancers elsewhere in the body. Nor do they cover benign tumours
such as meningiomas, which arise from the membranes surrounding the brain and spinal cord.
Table 1.1
Distribution of astrocytomas and oligodendrogliomas1
Tumour type
Percentage of all gliomas
Astrocytoma grade I (pilocytic)
4
Astrocytoma grade II (diffuse)
10
Astrocytoma grade III (anaplastic)
22
Glioblastoma multiforme (grade IV)
52
Oligodendroglioma grade II
3
Oligodendroglioma grade III (anaplastic)
4
Mixed oligoastrocytoma grade II & III
1
Not able to be graded
4
Brain cancers �are among the most devastating to patients and their carers because they affect the
organ that defines the self’.2 Although these cancers are not common, the average person years of life
lost (AYLL) due to primary brain cancers is estimated at 12 years per patient in Australia in 2001.3
This is much higher than the average for all cancers (three years) because these cancers tend to occur
in younger people.4 The extent of this loss can be seen in Figure 1.1, which shows that the primary
brain cancer is associated with the highest AYLL for the common cancers in Australia and the United
Kingdom.
Setting the scene
1
Figure 1.1
Average years of life lost for patients in Australia and the UK, 2001, by cancer type
25
AUS - AYLL
UK - AYLL
20
AYLL
15
10
5
m
a
an
o
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at
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os
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te
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Bl
a
Br
ea
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ec
ta
l
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om
ac
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ol
y
m
ia
U
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ea
w
n
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ne
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ck
le
m
ye
lo
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a
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om
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ey
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ae
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as
Pa
Le
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es
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ai
n
0
Sources: Burnet et al,5 Australian Institute of Health and Welfare (AIHW)6
Astrocytomas and oligodendrogliomas are the most common gliomas that arise from glial cells. They
make up about 40% of all CNS tumours7 and more than 60% of primary brain cancers.8 When glial
cells were named it was thought that their function was to provide the �glue’ which held neural tissue
together, to nourish nerve cells (neurons) and maintain nervous system immunity; recent work
suggests that normal glial cells influence synapses and modify neural connections, with implications
for learning and memory.9
Diffuse astrocytomas occur in any part of the CNS, infiltrate brain structures and can behave in
indolent or aggressive ways. They have the tendency to progress from lower (grade II) to higher
(grade IV, also called glioblastoma multiforme, GBM) grades of malignancy. However 70–95% of
GBM arise de novo, that is, without a precursor tumour.10 Grade I astrocytomas, also known as
pilocytic astrocytomas, occur in children and young adults, are less invasive than diffuse astrocytomas
and have a relatively good prognosis.
Oligodendrogliomas, which are thought to arise from the cells producing the myelin sheath that
insulates nerve fibres, are associated with longer survival than astrocytomas and can respond well to
chemotherapy.11,12 They often present after a long history of seizures and tend to be located towards
the surface of the cerebral hemispheres. The number of new cases each year appears to be rising
concurrently with a fall in the incidence of astrocytoma13,14 but this may be due to changing criteria
for histopathological diagnosis.
1.2
Incidence
There is a wide variety of CNS tumours, with the World Health Organisation listing more than 120
types.15 Many of the statistics described in this chapter refer to primary brain cancers, which comprise
the bulk of CNS cancers because numbers of other CNS cancers such as cancers of the spinal cord)
are too small to report reliably. An estimated 190,000 new cases occur per year worldwide. CNS
cancers make up less than 2% of all malignancies.16 Incidence does not vary greatly between regions
or populations.17 (The global incidence of benign CNS tumours is unknown as most cancer registries
do not collect these data.) According to the Australian Institute of Health and Welfare (AIHW), which
collects case notifications from all State Central Cancer Registries, in Australia 1369 or 6.8 per
2
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
100,000 people were diagnosed with primary brain cancer in 2004, the latest year for which national
figures are available.3 In comparison, approximately 161 new cases of breast cancer and 64 new cases
of colon cancer were diagnosed per 100,000 population that year. AIHW ranks CNS cancer as the
fourteenth most common cancer in Australia.18 In the Australian States and Territories, the agestandardised incidence of brain cancer in 2001 (the most recent year for which State data are
available) ranged from 6.3 per 100,000 in Western Australia and the Northern Territory to 7.5 per
100,000 in Victoria.4
1.3
Changes in incidence over time
Australia-wide, the crude incidence of primary brain and other CNS cancers increased 0.3% per year
from 1982 to 2004,3 similar to increases in some other countries.19,20 These increases have been
attributed to the introduction of computed tomographic scanning (CT) and magnetic resonance
imaging (MRI). CT scanning imaged some tumours better after the late 1970s,21 and after the mid
1980s MRI increased the diagnosis of low-grade astrocytoma which had been less visible using CT
scanning.22 After adjusting for patient age, incidence of brain cancer increased by an average of 0.1%
per annum in males and decreased by an average of 0.8% per annum in females between 1991 and
2001.4 The increased incidence over time was mostly in people over 65 years old, probably because
non-invasive CT and MRI has improved diagnosis in older people.23
1.4
Influence of age and sex
Primary brain cancer is most commonly diagnosed in childhood and in adults 45–70 years of age, of
both sexes. In children, brain cancers are the most common malignancy after leukaemia. Posterior
fossa tumours predominate in children, but cerebral hemisphere tumours predominate in adults. The
median age at diagnosis of brain cancers in Australia was 55–59 years for males and 60–64 for
females in 1999.23,24
Incidence rates are higher in males for primary CNS cancers (1.3:1), whereas females have a greater
incidence of meningiomas (around 1.5:1).25
1.5
Influence of socio-economic status and geographic
area
Australian studies have shown that survival of patients with cancers other than glioma varies
according to socio-economic strata (SES) and geographic differences.26–29 A recent report shows that
these factors also independently affect survival of patients with glioma in England and Wales30, and
suggests that chronic co-morbidities and differences in effectiveness of healthcare systems may be
responsible for these inequalities. There are no Australian data comparing survival of glioma patients
by SES or geographic location, but New South Wales data show no significant variation in survival
between Area Health Services.31
1.6
Mortality
The death rate from brain cancer is higher in developed countries than in the less-developed countries,
probably because of better detection of cases rather than worse treatment in the more developed
countries. Brain cancers rank 12th in order of cancer-related deaths in most developed countries16 and
10th in Australia.4 In Australia 1048 people died from brain cancer, that is, 2.9% of deaths from
malignancy, in 2004.3 Mortality fell by an average of 1.2% per year between 1994 and 2004 to 5.4
deaths per 100,000 in 2004.3 The median age at death was 60 years, the youngest age of the 14 cancer
types for which these data were reported.4
Setting the scene
3
1.7
Survival
According to the AIHW, 24% of Australians diagnosed with all brain cancers between 1992 and 1997
survived for five years.6 There was no increase in survival in Australia over the periods 1982–1986,
1987–1991 and 1992–1997.6 Relative survival of all patients diagnosed with brain cancer between
1997 and 2004 was 20% at five years and 16% at ten years.32
Younger age, good preoperative performance status and gross macroscopic resection have been
associated with longer survival in patients with astrocytoma and oligodendroglioma.33 After resection,
average survival for grade II astrocytomas reported internationally is around five to eight years,34,35
for grade III (anaplastic astrocytoma) about three years 36 and for grade IV (GBM) less than one
year.37 A recent Australian study reported all grades of Victorian glioma patients to have a median
survival of 9.2 (range 0–84+) months and GBM patients to have a median survival of 7.4 (range 0–84)
months.38 A long-term study of astrocytoma patients between 1980 and 2004 in Northern Sydney
reported median survivals of 64 months for grade II, 11 months for grade III and eight months for
GBM.39 These figures relate to patients treated before 2002 when treatment with concurrent
radiotherapy and chemotherapy was introduced40 (see Chapter 8 High-grade astrocytomas).
Reported survival times for oligodendrogliomas vary widely because of the low incidence of these
tumours, difficulties classifying them and various genetic subtypes.41 Low-grade oligodendrogliomas
are reported to have median survival times of up to ten years, while for anaplastic oligodendrogliomas
(grade III) median survival times range between one and seven years.42
1.8
Predisposing factors and causes
Many possible risk factors including diet, occupations, alcohol, tobacco, drugs and a history of
infection or trauma have been explored for evidence of a causal link with brain cancers, but the
associations seen are weak and inconsistent. Known predisposing factors for astrocytomas and
oligodendrogliomas include increased age, male sex and a rare familial (inherited) tendency. Rare
familial syndromes involving the nervous system include neurofibromatosis types 1 and 2, LiFraumeni and Turcot. Patients with these syndromes are at increased risk of developing gliomas.43
Ionising radiation44,45 has been convincingly recognised as a cause of brain tumours, but such cases
are rare46. For most patients no cause has been clearly identified—the vast majority of brain cancers
appear to arise randomly. Non-ionising radiation has been suspected as a cause of brain cancers for
many years, but studies in electrical workers and mobile phone users have shown either no effect or a
slight increase in incidence of benign brain tumours associated with prolonged use of old-style
analogue phones. Even those studies most recently available do not agree on evidence of an effect.47,48
Any radiation exposure from a mobile phone to the brain will be less than to the ear, because of the
inverse square law: as the distance from an energy source doubles, its effect is reduced to a quarter.49
1.9
Why we don’t know what causes primary brain cancer
There are three main reasons it has been difficult to determine the causes of astrocytomas and
oligodendrogliomas:
•
•
•
the heterogeneity of these tumours and an historical lack of specificity of diagnosis
small numbers of specific tumour subtypes
the use of retrospective study designs, particularly case-control studies.
Historically, epidemiological studies have classified all CNS cancers together because there was little
detail of the histopathological diagnosis available from cancer registries, which are the main source of
population-based ascertainment for research subjects. Mixing all CNS cancers together as if they all
share the same causal risk factors will diminish the chance of detecting any association that might be
specific to one tumour type. This problem is beginning to be addressed by recent studies that restrict
4
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
case ascertainment to glioma as a group. Much still needs to be done and it is hoped that our
increasing understanding of the molecular biology and genetics of gliomas may help define subtypes
with precision.
Even the most frequently diagnosed morphological subtypes of these tumours are not common, and
most can be considered rare. It is extremely difficult, therefore, to study sufficient numbers of cases
from which to draw statistically significant conclusions. The rapid fatality of many of these tumours
also biases studies towards those subjects that survive long enough to be interviewed.
Because of their rarity, the usual approach to researching the epidemiology of brain cancers has been
to conduct a case-control study, which is an observational study in which the occurrence of an
attribute in people with the disease (or other outcome) of interest in a population is compared with the
occurrence of the same attribute in the same population at large. Those with the disease or (or other
outcome) of interest are called cases. The occurrence of the attribute in the population at large is
determined in a sample of the population known as the control group. The design of case-control
studies varies with respect to the selection of cases and controls. The problems with this approach are
many, but for brain cancers in particular there is the possibility of the cancer and/or its treatment
directly affecting the ability of the subject to recall past events. In this situation, the differences in
information obtained from cases and controls can cause bias in estimating risks that may lead to
spurious findings.
Given the large number of ongoing prospective studies internationally, plans are being made to pool
glioma cases for analysis thus avoiding the problem of recall bias. Research into genetic mechanisms
involved in brain tumour biology is very active. Future gains in our understanding of the molecular
pathology of gliomas could assist the search for causes by increasing our ability to classify gliomas in
a more biologically meaningful way.
1.10
Prevention
Because no causes have been convincingly identified for astrocytomas and oligodendrogliomas, no
specific preventive measures can be recommended.
1.11
Screening
Screening is most effective for cancers that occur commonly; where there is a cheap, specific and safe
test that detects the tumour at an early stage; and where an effective treatment exists that works best
when the tumour is found in an early stage. Although screening is available for cervical, breast and
bowel cancer in Australia, there is no known cost-effective way to screen for brain cancers because
they are rare and early detection does not greatly increase the benefit of treatment. An exception is the
potential use of genetic testing to identify patients with neurofibromatosis type 1, who are at risk of
developing optic glioma, a slow-growing tumour which can impair vision.50
Setting the scene
5
Key points:
•
Astrocytomas and oligodendrogliomas comprise the largest proportion of primary CNS
cancers.
•
Primary CNS cancers are diagnosed in 7/100,000 Australians each year, compared with
colon cancer 60/100,000/year.
•
Although uncommon, CNS cancers are associated with the highest person years of life
lost (PYLL) of all major cancers—on average 12 years per patient.
•
Astrocytomas and oligodendrogliomas have a tendency to progress to higher grades of
malignancy over time.
•
Gliomas are more common in males. Median age at diagnosis is 55–59 years in males,
60–64 years in females.
•
Incidence has increased slightly over the past twenty years, probably due to increased
life span, improved imaging and more investigation in elderly patients.
•
Incidence of glioma does not vary much between geographical areas.
•
Median survival after resection is 5–8 years for low-grade astrocytoma, three years for
patients with anaplastic astrocytoma, about one year for patients with GBM, up to ten
years for low-grade oligodendroglioma and 1–7 years for anaplastic oligodendroglioma.
Younger age, good preoperative performance status and gross macroscopic resection
are associated with longer survival.
•
Nearly all CNS cancers arise randomly. The only known cause is ionising radiation.
•
Known risk factors for developing glioma are increased age, male sex and rare familial
genetic syndromes.
•
Except possibly for neurofibromatosis type 1, no screening test is available for glioma as
early detection does not increase the benefit of treatment.
1.12
Some useful links
1.
Independent Expert Group on Mobile Phones. Report of the Group (The Stewart Report):
http://www.iegmp.org.uk/documents/iegmp_5.pdf
2.
Australian Radiation Protection and Nuclear Safety Agency has information about mobile
phones and electromagnetic radiation: http://www.arpansa.gov.au/mph1.htm
3.
The Cancer Council of Australia has general information about cancer, including dietary
advice. http://www.cancer.org.au/
4.
NSW Cancer Institute Incidence and Mortality Report 2004:
http://www.cancerinstitute.org.au/cancer_inst/publications/pdfs/IncidenceMortalityReport200
4.pdf
References
1
6
Smith SF, Simpson JM, Sekhon LH. What progress has been made in surgical management of
patients with astrocytoma and oligodendroglioma in Australia over the last two decades? J
Clin Neurosci 2005; 12(8):915–920.
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
2
Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC et al. The
WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 2002;
61(3):215–225.
3
Australian Institute of Health and Welfare. ACIM (Australian Cancer Incidence and
Mortality). 2007. Canberra, AIHW.
4
Australian Institute of Health and Welfare. Cancer in Australia 2001. 28. 2004.Canberra.
AIHW
5
Burnet NG, Jefferies SJ, Benson RJ, Hunt DP, Treasure FP. Years of life lost (YLL) from
cancer is an important measure of population burden--and should be considered when
allocating research funds. Br J Cancer 2005; 92(2):241–245.
6
Australian Institute of Health and Welfare AAoCR. Cancer Survival in Australia, 2001. Part
1: National Summary Statistics. 2001. Canberra, Australian Institute of Health and Welfare.
Cancer Series No. 18.
7
CBTRUS (2004). Statistical Report: Primary Brain Tumors in the United States, 1997–2001.
2005. Central Brain Tumor Registry of the United States.
8
Pathology & Genetics of Tumours of the Nervous System. Lyon: IARC Press, 2000.
9
Fields RD. The other half of the brain. Scientific American 2004;(April):27–33.
10
Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL et al. Genetic
pathways to glioblastoma: a population-based study. Cancer Res 2004; 64(19):6892–6899.
11
Fortin D, Cairncross GJ, Hammond RR. Oligodendroglioma: an appraisal of recent data
pertaining to diagnosis and treatment. Neurosurgery 1999; 45(6):1279–1291.
12
Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR et al.
Specific genetic predictors of chemotherapeutic response and survival in patients with
anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90(19):1473–1479.
13
Perry A. Oligodendroglial neoplasms: current concepts, misconceptions, and folklore. Adv
Anat Pathol 2001; 8(4):183–199.
14
Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK. Improving diagnostic
accuracy and interobserver concordance in the classification and grading of primary gliomas.
Cancer 1997; 79(7):1381–1393.
15
Pathology & Genetics of Tumours of the Nervous System. Lyon: IARC Press, 2000.
16
Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer Incidence, Mortality and
Prevalence Worldwide. 5, Version 2.0. 2004. Lyon, IARC Press. IARC CancerBase. 8-62005.
17
Kleihues P. Tumours of the Nervous System. In: Stewart BW, Kleihues P, editors. World
Cancer Report. Lyon: IARC Press, 2003: 265–269.
18
Australian Institute of Health and Welfare, Australasian Association of Cancer Registries
(AACR). Cancer in Australia: an overview, 2006. AIHW cat. no. CAN 32 – Cancer Series
Number 37. Canberra: Australian Institute of Health and Welfare, 2007.
19
Desmeules M, Mikkelsen T, Mao Y. Increasing incidence of primary malignant brain tumors:
influence of diagnostic methods. J Natl Cancer Inst 1992; 84(6):442–445.
Setting the scene
7
20
Helseth A, Langmark F, Mork SJ. Neoplasms of the central nervous system in Norway. II.
Descriptive epidemiology of intracranial neoplasms 1955–1984. APMIS 1988; 96(12):1066–
1074.
21
McKinley BP, Michalek AM, Fenstermaker RA, Plunkett RJ. The impact of age and sex on
the incidence of glial tumors in New York state from 1976 to 1995. J Neurosurg 2000;
93(6):932–939.
22
Gurney JG, Kadan-Lottick N. Brain and other central nervous system tumors: rates, trends,
and epidemiology. Curr Opin Oncol 2001; 13(3):160–166.
23
Tracey EA, Supramaniam R, Chen W. Cancer in New South Wales: Incidence and Mortality
2001. 2003. Sydney, The Cancer Council NSW. 1-6-2005.
24
Chang D. Statistics on incidence, survival rates and mortality associated with brain tumors in
Australia. 2003. Canberra, ACT, National Cancer Statistics Clearing House, Australian
Institute of Health and Welfare.
25
Louis DN, Scheithauer BW, Budka H, von Deimling A, Kepes JJ. Meningeal Tumours. In:
Kleihues P, Cavenee WK, editors. Pathology and Genetics of Tumours of the Nervous
System. Lyon: IARC Press, 2000: 176–184.
26
Coleman MP, Babb P, Sloggett A, Quinn M, De SB. Socioeconomic inequalities in cancer
survival in England and Wales. Cancer 2001; 91(1 Suppl):208–216.
27
Galobardes B, Costanza MC, Bernstein MS, Delhumeau C, Morabia A. Trends in risk factors
for lifestyle-related diseases by socioeconomic position in Geneva, Switzerland, 1993–2000:
health inequalities persist. Am J Public Health 2003; 93(8):1302–1309.
28
Law MR, Morris JK. Why is mortality higher in poorer areas and in more northern areas of
England and Wales? J Epidemiol Community Health 1998; 52(6):344–352.
29
O'Hanlon S, Forster DP, Lowry RJ. Oral cancer in the North-East of England: incidence,
mortality trends and the link with material deprivation. Community Dent Oral Epidemiol
1997; 25(5):371–376.
30
Tseng JH, Merchant E, Tseng MY. Effects of socioeconomic and geographic variations on
survival for adult glioma in England and Wales. Surg Neurol 2006; 66(3):258–263.
31
Tracey EA, Coates M, Ryan M, Manefield M. NSW Cancer Registry Statistical Reporting
Module. Internet . 2005. NSW Cancer Institute.
32
Australian Institute of Health and Welfare, Cancer Australia, Australasian Association of
Cancer Registries. Cancer Survival and Prevalence in Australia: cancers diagnosed from 1982
to 2004. Cancer Series no. 42 Cat no. CAN 38. 2008. Canberra, AIHW.
33
Laws ER, Parney IF, Huang W, Anderson F, Morris AM, Asher A et al. Survival following
surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma
Outcomes Project. J Neurosurg 2003; 99(3):467–473.
34
Pathology & Genetics of Tumours of the Nervous System. Lyon: IARC Press, 2000.
35
Reifenberger G, Collins VP. Pathology and molecular genetics of astrocytic gliomas. J Mol
Med 2004; 82(10):656–670.
8
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
36
Donahue B, Scott CB, Nelson JS, Rotman M, Murray KJ, Nelson DF et al. Influence of an
oligodendroglial component on the survival of patients with anaplastic astrocytomas: a report
of Radiation Therapy Oncology Group 83–02. Int J Radiat Oncol Biol Phys 1997; 38(5):911–
914.
37
Reifenberger G, Collins VP. Pathology and molecular genetics of astrocytic gliomas. J Mol
Med 2004; 82(10):656–670.
38
Rosenthal MA, Drummond KJ, Dally M, Murphy M, Cher L, Ashley D et al. Management of
glioma in Victoria (1998–2000): retrospective cohort study. Med J Aust 2006; 184(6):270–
273.
39
Smith SF, Simpson JM, Sekhon LH. What progress has been made in surgical management of
patients with astrocytoma and oligodendroglioma in Australia over the last two decades? J
Clin Neurosci 2005; 12(8):915–920.
40
Stupp R, Dietrich PY, Ostermann KS, Pica A, Maillard I, Maeder P et al. Promising survival
for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation
plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 2002; 20(5):1375–
1382.
41
Koeller KK, Rushing EJ. From the archives of the AFIP: Oligodendroglioma and its variants:
radiologic–pathologic correlation. Radiographics 2005; 25(6):1669–1688.
42
Hartmann C, Mueller W, von DA. Pathology and molecular genetics of oligodendroglial
tumors. J Mol Med 2004; 82(10):638–655.
43
Pathology & Genetics of Tumours of the Nervous System. Lyon: IARC Press, 2000.
44
Brada M, Ford D, Ashley S, Bliss JM, Crowley S, Mason M et al. Risk of second brain
tumour after conservative surgery and radiotherapy for pituitary adenoma. BMJ 1992;
304(6838):1343–1346.
45
Shore RE, Moseson M, Harley N, Pasternack BS. Tumors and other diseases following
childhood x-ray treatment for ringworm of the scalp (Tinea capitis). Health Phys 2003;
85(4):404–408.
46
Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M et al. Second
malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor
study. J Natl Cancer Inst 2001; 93(8):618–629.
47
Mobile phones and brain tumours: is there a risk? When will we know? Glioma 2005: The
Future; 05 Mar 17; 2005.
48
Hardell L, Mild KH, Kundi M. Re: Long-term mobile phone use and brain tumor risk. Am J
Epidemiol 2005; 162(6):600–601.
49
Panter R. Electromagnetic Radiation from TV and Mobile Phone Towers: Health Aspects.
Internet search: Australian Parliamentary Library Current Issues Brief 26 1996–97. 2001.
Commonwealth of Australia. 27-3-2006.
50
Field M, Shanley S, Kirk J. Inherited cancer susceptibility syndromes in paediatric practice. J
Paed Child Health. In press.
Setting the scene
9
2
APPROACH TO THE PATIENT
2.1
Issues facing patients
A diagnosis of a brain tumour can result in a broad range of complex physical, cognitive and
psychological symptoms. The ensuing functional impairment, loss of independence and potentially
severe disabilities are distressing for patients, their families and care givers. These issues are
expanded in Chapter 12 Psychosocial care.
There are specific challenges that arise when a patient is diagnosed with a brain tumour that are not as
commonly encountered in the management of other solid tumours.
Specific symptoms commonly experienced by patients as a direct result of brain tumours include
problems with memory (affecting comprehension and compliance), impaired judgement, and
personality changes. These are often compounded by limited insight. In addition, poor mobility,
weakness, speech impairments (such as aphasia), impaired vision, and seizures pose considerable
difficulties.
Health professionals involved in the care of patients with brain tumours must also be aware of the
potential toxicities of treatments. For example, treatment with steroids may be associated with
emotional lability, insomnia or reversal of sleep–wake cycle, high blood sugars (or exacerbation of
existing diabetes), and steroid myopathy exacerbating mobility problems. Similarly, anticonvulsants,
oral chemotherapy, antiemetics, aperients, prophylactic antibiotics and anticoagulants may cause sideeffects and interact with medications for co-morbid conditions.
2.2
Issues facing carers
Family members and carers of patients with brain tumours face a number of unique challenges. Carers
often assume a major responsibility in coordination of the patient’s care, which may involve extensive
travel for specialist treatment and in cases of the patient’s cognitive impairment, the carer may have a
central role in communication with health professionals and in decision-making. It is important not to
overlook the effect of practical adjustments that have to be made, for example, modifications to
housing to allow for wheelchair access. Especially for younger patients with a mortgage and
dependent children, the inability to work may pose significant financial hardship, which is
exacerbated if their partner is unable to work because of caring responsibilities. It is important that
clinicians ensure all carers have access to a person (such as a social worker) who has a clear
understanding of the available services–health, financial (eg availability of carer’s pension, and early
access to superannuation) and social–that may be appropriate for individual patients.
Key point:
•
The approach to the patient must include recognition of the concerns of family members
and caregivers and incorporate attention to complex medical and psychosocial issues.
2.2.1
Access to treatment
The care pathway for patients may be complex because of the number of health professionals
involved, and the potential for geographical separation of neurosurgical, chemotherapy and
radiotherapy treatment centres for a large proportion of those diagnosed. The period from initial
presentation of symptoms to diagnosis and subsequent treatment all add significantly to individual and
collective stresses and anxiety experienced by the patient and family.1
Following initial treatment many patients may experience a lengthy period of both physical and
cognitive deterioration, often without referrals to timely and appropriate support services.
10
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Assessment and management of complex cognitive, emotional, personality and behavioural problems
from specialist psycho-oncologists, neuropsychologists and/or neuropsychiatrists should be offered if
readily available. Assessment should occur on a continuing basis, including monitoring of any
cognitive and personality changes according to disease progression.
2.2.2
Multidisciplinary approach
There are no prospective trials that have examined the role and effectiveness of multidisciplinary
teams in the field of neuro-oncology. A retrospective comparison of two hospitals with and without
multidisciplinary care (MDC) demonstrated better clinical quality outcomes for brain tumour patients
managed by MDC. MDC patients were more likely to receive post-operative imaging and early
radiotherapy and had improved median survival.2 The model of multidisciplinary care is well
established in many areas, for example, the care of breast cancer patients (NBOCC).3 Expert opinion
states that the optimal care of all patients with a brain tumour should be delivered and coordinated by
a multidisciplinary team. The team members can include: neurosurgeon, radiation oncologist, medical
oncologist, neurologist, endocrinologist, rehabilitation physician, palliative care physician, clinical
care coordinator, social worker, occupational therapist, physiotherapist, community nurse, inpatient
team (registrars, nurses, etc), dietician and others. Brain tumour care coordinators and brain nurse
practitioners are not widely available in Australia, but would be desirable in most settings.
Involvement of community and palliative care services may be required soon after diagnosis for
patients with high-grade tumours. The social worker is also an integral part of the team and will
coordinate financial and emotional support. The patient may need a disability allowance, a carer’s
allowance, access to superannuation or a variety of other services. The general practitioner (GP)
should also be regarded as an integral part of the team and may provide the long-term continuity of
care.
Timely communication between health-care professionals is particularly important for patients with
brain tumours whose care pathway is often complex. All team members need appropriate accurate
knowledge and understanding of the patient’s current situation so they can facilitate involvement of
family and caregivers in management and decision-making and so that clear consistent information is
given to patient, family and caregivers. Members of the team need to be aware of any aspects of the
individual’s and family’s culture, religious beliefs or social background that may affect their response
to information.
Good team communication may �maximise the technical synergy of care’.4 Information should be
forwarded to the patient’s GP and other treating clinicians as soon as practicable after consultations,
including relevant details regarding diagnosis, clinical findings, future tests/test results, treatment
recommendations, likely side-effects and prognosis5 and the response of the patient and family to the
information given.
2.2.3
Coordination of care
A patient may be treated by many different health professionals during the course of their illness, and
effective coordination of care may improve the outcome. Continuity of care is considered important;
frequent staff changes are disruptive and counter-productive, both for the patient and from the
professional point of view.
To help maintain continuity of care, it is suggested there be a designated lead clinician who may
change with time and who bears overall responsibility for the relationship with the patient. The choice
of the person to coordinate care should be made by the patient in conjunction with their general
practitioner and other specialists.6,7
2.3
Specific communication issues: information provision
There are different challenges at different junctures of the disease journey.
Approach to the patient
11
2.3.1
Diagnosis
Initial consultation
It is essential that the patient and their support person(s) be informed from initial presentation that an
accurate diagnosis can only be obtained when the test results are reviewed by the treatment team.
Frozen sections should not be relied upon for diagnosis. Frozen section is only a technical aid during
resection. Tissue confirmation of diagnosis may not be available for up to a week (occasionally
longer) after the surgical procedure due to the need for special histopathological stains and possibly
specialist neuropathology review. Some molecular or genetic testing will take longer than a week.
Studies have shown that only a proportion of the information given in the initial consultation is
remembered8 hence it is important to check understanding, repeat information and provide
communication aids such as CDs, DVDs, audiotapes or personalised letters from the consultation,
although they may not increase knowledge or recall.9,10 Educational resources should be readily
available and provide clear accurate and relevant information about each malignant tumour type and
explanations of commonly used terms and patterns of care. Involving consumers in developing patient
information materials can improve the clarity and relevance of materials, and can improve people’s
knowledge without increasing their anxiety about medical procedures.11 Details should be provided
about local and national societies, appropriate websites and other relevant publications including selfhelp and support in their area, particularly voluntary organisations that have relevant helpline and
information services.
At each stage of the patient care pathway, information on any relevant clinical trials, research on a
particular treatment and palliative care services should all be available for patients, their families and
caregivers.
Interpreter services should be used when lack of English proficiency may inhibit communication
between the patient and their health-care provider. Furthermore, it may be appropriate to seek the
assistance of some culturally and linguistically diverse professionals (eg Aboriginal and Torres Strait
Islander) in circumstances where cultural differences inhibit effective communication. The interpreter
should be a professional and not a family member.
Breaking bad news
Breaking bad news in language the patient understands is usually the responsibility of the lead
clinician who knows the patient and is likely to be actively involved in the ongoing management
plan.12 Evidence suggests that most cancer patients wish to be fully informed of all available
information and they usually want a close relative or friend present at the initial consultation.13
Patients report that the subsequent discussions about treatment plans and what the diagnosis means
are at least as important, if not more important than, the disclosure of the initial diagnosis.14
It can be very confronting to a clinician when a family, with good intentions, wishes to protect the
patient from disclosure of their diagnosis or from the decision-making process. However, the primary
responsibility of the clinician is to the individual patient. Where culturally appropriate, the patient
should ideally be asked about their preferences for the provision of information.
There will be several occasions during the care of an individual with a glioma that bad news needs to
be delivered.
These points in time can include:
•
initial diagnosis
•
at time(s) of disease progression
12
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
•
at the time no more active treatment will be offered (due to poor performance status or not having
further options available)
•
at a time when the family do not feel they can continue to care for the patient at home.
Recommended steps for breaking bad news
Prior to discussing the diagnosis
•
Ensure the news is given in person in a quiet private place and allow enough uninterrupted time.
•
Encourage a second person to be present if appropriate. In the presence of cognitive impairment
this is essential.
•
Arrange to provide other methods to convey information such as written material, DVDs,
videotapes, etc.
When providing the information
•
Assess the person’s understanding of their condition and their personal preferences for
information.
•
Briefly explain the process by which the diagnosis was reached.
•
Provide information simply and honestly, using lay terms without euphemisms.
•
Avoid giving the message that �nothing can be done’.
•
Clearly indicate that the patient will have the final decision regarding their care.
Emotional and supportive role
•
Encourage the person to express their feelings and talk about fears or concerns, and respond with
empathy.
•
Address disturbing or embarrassing topics directly, with sensitivity.
•
Assess the type and level of assistance that may be required, such as financial assistance or
transport services.
•
Provide information about support services.
Concluding the discussion
•
Summarise the main points of the consultation and check the person understands.
•
Ask if there is anything further the individual would like to discuss.
•
Offer assistance to tell others the difficult news.
•
Indicate your availability for contact to address questions or concerns.
After discussing diagnosis or recurrence
•
Document information given to the person and family members.
•
Let others, especially the person’s general practitioner, know the extent of the information given
and your perception of the person’s understanding.
Adapted from Clinical Practice Guidelines for the Psychosocial Care of Adults with Cancer 2003.7 Reproduced with
permission
Approach to the patient
13
Families, partners and children
It is appropriate for clinicians who break the news of the diagnosis to the patient to ask about the
family’s and children’s adjustment, clarify what assistance may be required in discussing diagnosis
and treatment with family and children, and facilitate referral for information and support as needed.
When a patient clinically does better than expected, this can pose certain unexpected challenges such
as the need for discussion about ongoing treatment (and limitations of treatment) and issues such as
carer fatigue or �burn-out’.
For patients with young children the resource produced by The Cancer Council of New South Wales:
When a parent has cancer: how to talk to your kids. A guide for parents with cancer, their families and
friends 200515 should be provided to the patient and the partner/carer.
2.3.2
Discussing prognosis
Gliomas are generally incurable. High-grade gliomas generally have a short prognosis (years to a few
months depending on whether grade III anaplastic astrocytoma or IV glioblastoma). The prognosis of
a low-grade tumour can be difficult to predict as it is difficult to know which patients have tumours
that will transform into higher-grade tumours and it is also difficult to predict when such a
transformation will take place. The discussion will be different according to whether one is discussing
prognosis with a patient with a low-grade glioma (longer prognosis usually) or a patient with a highgrade glioma (who will have shorter prognoses on average). More detail on prognosis is provided in
Chapter 1 Setting the Scene and in Chapters 7 Low-grade astrocytomas, 8 High-grade astrocytomas
and 9 Oligodendrogliomas.
Most patients want to receive prognostic information because it helps in their decision-making.16-18,1921
Key points to consider in discussing prognosis include:
Timing
It is important at the time of diagnosis (once the pathology results have been reviewed) to have a
discussion relating to prognosis that is tailored to the patient’s (and carer’s) needs.
Tailoring to the individual
Some people desire as much information as possible; others prefer minimal information. A patient’s
need for information may alter over time as the treatment proceeds and symptoms fluctuate. The
safest option it to check the patient’s preferences for information and review this over time.
Information will need to be tailored to aid understanding if the patient has cognitive impairment.
Relatives often give a guide to the patient’s tolerance for information and the family’s wishes should
be considered as well as the cultural context. However, the patient’s autonomy and rights are
paramount.
Language
Information should be given honestly in simple language without use of jargon. Vagueness and
obscurity make a difficult situation worse.22 It is useful to give average and longest survival times,
emphasising a range rather than a single time point, and to present information in a variety of formats,
for example words, statistics or graphs.18
Maintaining hope
Most patients prefer that their clinicians speak plainly and in clear language. A study of patients with
advanced cancer found that 82% of patients did not consider that the use of euphemisms by their
doctor would promote their hope.23 In this study, physician behaviours found to be more likely to
promote hope included treating the person as an individual, being realistic about the likely future,
14
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
placing emphasis on what can be done rather than what can’t be done, and checking how the person is
feeling.
Emotional support
It is extremely important that patients are allowed to express their feelings and that these expressions
receive an empathetic response.
Consensus guidelines provide supporting evidence and practical strategies to assist health
professionals in discussing prognosis.17,18,24
Discussing treatment options
The National Health and Medical Research Council (NHMRC) General guidelines for medical
practitioners on providing information to patients25 state that patients are entitled to make their own
decisions about treatments or procedures and should be given adequate information on which to base
those decisions:
•
Information should be provided in a form and manner which helps patients understand the
problem and treatment options available, and that is appropriate to the patient’s
circumstances, personality, expectations, fears, beliefs, values and cultural background
•
Doctors should give advice, but should not coerce
•
Patients should be encouraged to make their own decisions
•
Patients should be frank and honest in giving information about their health, and doctors
should encourage them to do so
The medico–legal aspects of competency are covered in Chapter 12 Psychosocial care. The medico–
legal aspects regarding ability to consent to participate in a clinical trial are in Chapter 3 Clinical trials
and research.
Decision-making
There has been a trend for patients in all health settings, including oncology, to be increasingly
involved in decisions regarding their treatment.26 However decision-making is often complex, and on
occasions the risks and benefits of particular treatments may be difficult to predict.27,28 For some
patients, involvement in decision-making is unfamiliar29 and they may find decision-making more
difficult because of the stress surrounding diagnosis.
It is important that any discussion between doctor and patient should attempt to establish the patient’s
values and preferences for involvement in decision-making. For shared decision-making to be
achieved, patients need to understand the information presented, ask questions to clarify outstanding
issues, weigh up the available treatment options and state their preferred option. In a shared decisionmaking model, the patient and oncologist make the final treatment decision together, having
considered the patient’s values, the risks and benefits of alternative treatment options and through a
process of negotiation.30,31
While shared decision-making is generally considered to be optimal, there may be particular barriers
to shared decision-making in neuro-oncology. Doctors must be able to translate the scientific findings
of research into lay language that is relevant to the particular patient’s situation32, however if the
patient has cognitive impairment this is complex to do. There is evidence that many patients find it
difficult to define their preferences for information and involvement in decision-making, however
cognitive impairment is common for patients with brain tumours33 and this may impede their ability to
communicate their own values and preferences. In the most extreme instances, patients’ level of
cognitive compromise can render them incapable of making decisions. However, it remains important
Approach to the patient
15
to ensure that patients are as involved in the decision-making process as they are cognitively able to
be. A number of measurement tools exist to facilitate accurate assessment of patients’ competence.
Taphoorn and Klein34 recommend the use of a comprehensive series of tests which cover the different
cognitive domains including memory, attention, orientation, language abilities and executive function.
Given the poor prognosis and significant potential for cognitive impairment, it is particularly
important in neuro-oncology to pre-empt difficulties which might arise in relation to the decisionmaking capacity of these patients. While some patients have considered in advance the nature of
treatments that they would want should they become incapable of making a decision, such orders are
often poorly understood and not extensively exercised35,36 so it is important for their neurosurgeon or
oncologist to ask about any existing advanced directives and to clarify any ambiguous points. The
ideal approach is for the oncologist to introduce the subject of decision-making and assist the patient
in expressing their wishes while competent to do so, rather than reacting only when faced with the
patient’s incapability. Additionally, it is helpful to have the patient nominate a surrogate decisionmaker (usually a close family member) who could make decisions on the patient’s behalf should the
patient become incapacitated and who is aware of the patient’s wishes. Ideally, this person would be
involved in medical discussions with the patient and the doctor as early as possible in the illness
trajectory. If a patient nominates a person to make treatment decisions on their behalf, this is
considered a suitable alternative to informed consent.
Although many clinicians may feel that discussing these issues is confronting, in fact most patients
feel relieved to be able to express their concerns, and less distressed that they are placing a burden of
responsibility on family members. After open discussion, family members often feel more confident
that they will be able to �do the right thing’ to respect the values and wishes of the patient, rather than
struggling with doubt and guilt, which is common if the patient has not expressed their views.
If the patient is incapable, a number of options are available to oncologists to determine the
appropriate medical management. These options vary between jurisdictions and are described in detail
in Chapter 12 Psychosocial care.
Key point:
•
Cognitive deficits are common with gliomas and can impair patients' abilities to
comprehend information and specifically their capacity to provide informed consent for
treatment. In the area of shared decision-making, the guiding principles should be to
respect patients’ autonomy and to act in patients’ best interests.
While conflict that cannot be resolved through a process of shared decision-making with the patient or
their surrogate is likely to be rare, given the nature of glioma these situations may arise more often
than in many areas of medicine.
16
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Good practice points:
•
Present information in a clear and unambiguous way. Avoid medical jargon and use lay
terms where possible.
•
Encourage the patient to ask questions about any aspects of the treatment/s.
•
Elicit the patient’s values and preferences.
•
Negotiate a treatment decision with the patient.
•
Where possible, include another person in the room during your consultation with the
patient (essential if there is any degree of cognitive impairment).
•
Where possible, aim to discuss while the patient is still competent to make decisions the
sort of treatment and care they would like to receive if their illness progresses.
•
Ask the patient to nominate a surrogate decision-maker should their condition
deteriorate and encourage the patient to discuss their wishes about treatment with this
person.
2.4
Other aspects of approach to the patient
2.4.1
Second professional opinion
Patients have the right to obtain a second opinion at any time. A second opinion may help patients to
clarify questions and to decide which doctor they prefer to manage their condition and which course
of treatment to follow. It can also reinforce the accuracy of advice already given, and enhance the
patient’s confidence. Doctors should cooperate fully in providing both a referral and all relevant
information.37
2.4.2
Preparing patients for potentially threatening procedures and
treatment
People diagnosed with a brain tumour may undergo a number of traumatic medical procedures and
interventions, such as surgery, biopsies, radiotherapy and chemotherapy. Provision of procedural
information about the treatment plan significantly reduces emotional distress and anticipatory sideeffects, and improves psychological and physical recovery.38,39 Examples of procedural information
include discussion of practical issues such as where the procedure will take place, what it involves, for
example the noise associated with an MRI, how long it will last, etc. This information can be provided
by a clinician or allied health professional40, booklets41, video information42, models or images. The
addition of sensory information can further reduce anxiety.34 Sensory information refers to what the
person is likely to experience and feel during the procedure, such as discomfort or pain, including
possible emotional responses.
2.4.3
Supportive care
Supportive care is an encompassing term for the services provision from a wide range of health-care
professionals to address the changing needs of patients, families and caregivers throughout the patient
journey. The way a clinician and treatment team relates to and communicates with a patient can
significantly benefit the patient and their family.43 Encouraging patients to talk about their concerns is
important, as there is evidence that this reduces patient distress.44 Specific strategies for provision of
support are described in more detail in Chapters 12 Psychosocial care and 13 Rehabilitation. In
addition, there is clear evidence that training in communication skills improves the ability of health
professionals to respond to the emotional concerns of patients.45
Approach to the patient
17
2.5
Other challenging communication issues
There are many other communication challenges for the health professionals caring for a patient with
a brain tumour.
For example, many patients do not cope well with the discussion around no longer being able to drive
if they have active tumour (see Chapter 13 Rehabilitation). Other challenging communication issues
may include placement issues (eg whether a patient can be managed at home versus care in a nursing
home, which can cause arguments within families) or the discussion of advanced directives (see
Chapter 15 Palliative Care).
References
1
Grant R. Overview: Brain tumour diagnosis and management/Royal College of Physicians
guidelines. J Neurol Neurosurg Psychiatry 2004; 75 Suppl 2:ii18-ii23.
2
Back MF, Ang EL, Ng WH, See SJ, Lim CC, Tay LL et al. Improvements in quality of care
resulting from a formal multidisciplinary tumour clinic in the management of high-grade
glioma. Ann Acad Med Singapore 2007; 36(5):347-351.
3
National Breast Cancer Centre. Making multidisciplinary cancer care a reality: A national breast
cancer forum series. Report and Recommendations. 2006. National Breast Cancer Centre.
4
Penson RT, Kyriakou H, Zuckerman D, Chabner BA, Lynch TJ, Jr. Teams: communication in
multidisciplinary care. Oncologist 2006; 11(5):520-526.
5
Tattersall MH, Griffin A, Dunn SM, Monaghan H, Scatchard K, Butow PN. Writing to referring
doctors after a new patient consultation. What is wanted and what was contained in letters from
one medical oncologist? Aust N Z J Med 1995; 25(5):479-482.
6
Yates P. Cancer Care Coordinators: Realising the Potential for Improving the Patient Journey.
Cancer Forum 2004; 28(2):128-132.
7
National Breast Cancer Centre, National Cancer Control Initiative. Clinical practice guidelines
for the psychosocial care of adults with cancer. 1-242. 2003. Canberra, NHMRC National
Health and Medical Research Council.
8
Dunn SM, Butow PN, Tattersall MH, Jones QJ, Sheldon JS, Taylor JJ et al. General
information tapes inhibit recall of the cancer consultation. J Clin Oncol 1993; 11(11):22792285.
9
Tattersall MH, Butow PN, Griffin AM, Dunn SM. The take-home message: patients prefer
consultation audiotapes to summary letters. J Clin Oncol 1994; 12(6):1305-1311.
10
Olver IN, Whitford HS, Denson LA, Peterson MJ, Olver SI. Improving informed consent to
chemotherapy: a randomized controlled trial of written information versus an interactive
multimedia CD-ROM. Patient Educ Couns 2009; 74(2):197-204.
11
Nilson ES, Myrhaug HT, Johansen M, Oliver S, Oxman AD. Methods of consumer
involvement in developing health care policy and research, clinical practice guidelines and
patient information material. Cochrane Database of Systematic Reviews [3]. 2006.
12
Girgis A, Sanson-Fisher RW. Breaking bad news: consensus guidelines for medical
practitioners. J Clin Oncol 1995; 13(9):2449-2456.
18
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
13
Butow PN, Kazemi JN, Beeney LJ, Griffin AM, Dunn SM, Tattersall MH. When the diagnosis
is cancer: patient communication experiences and preferences. Cancer 1996; 77(12):2630-2637.
14
Lind SE, DelVecchio Good MJ, Seidel S, Csordas T, Good BJ. Telling the diagnosis of cancer.
J Clin Oncol 1989; 7(5):583-589.
15
The Cancer Council of New South Wales. When a parent has cancer: how to talk to your kids.
A guide for parents with cancer, their families and friends. 2005.
16
Clayton JM, Hancock K, Butow PN, Tattersall MH, Currow C. Clinical Practice Guidelines for
communicating prognosis and end-of-life issues with adults in the advanced statges of a lifelimiting illness, and their caregivers. Medical Journal of Australia 2007; 186(12):S77-S108.
17
Lobb E, Kenny DT, Butow PN, Tattersall M. Women's preferences for discussion of prognosis
in early breast cancer. 1998. Sydney, National Breast Cancer Centre.
18
Lobb E, Kenny DT, Butow PN, Tattersall M. Talking about prognosis with women who have
early breast cancer: what they prefer to know and guidelines to help explain it effectively.
1998. Sydney, National Breast Cancer Centre.
19
Davey HM, Butow PN, Armstrong BK. Cancer patients' preferences for written prognostic
information provided outside the clinical context. Br J Cancer 2003; 89(8):1450-1456.
20
Kaplowitz SA, Campo S, Chiu WT. Cancer patients' desires for communication of prognosis
information. Health Commun 2002; 14(2):221-241.
21
Hagerty RG, Butow PN, Ellis PA, Lobb EA, Pendlebury S, Leighl N et al. Cancer patient
preferences for communication of prognosis in the metastatic setting. J Clin Oncol 2004;
22(9):1721-1730.
22
Dunn SM, Patterson PU, Butow PN, Smartt HH, McCarthy WH, Tattersall MH. Cancer by
another name: a randomized trial of the effects of euphemism and uncertainty in communicating
with cancer patients. J Clin Oncol 1993; 11(5):989-996.
23
Hagerty RG, Butow PN, Ellis PM, Lobb EA, Pendlebury SC, Leighl N et al. Communicating
with realism and hope: incurable cancer patients' views on the disclosure of prognosis. J Clin
Oncol 2005; 23(6):1278-1288.
24
Clayton JM, Hancock K, Butow PN, Tattersall MH, Currow C. Clinical Practice Guidelines for
communicating prognosis and end-of-life issues with adults in the advanced statges of a lifelimiting illness, and their caregivers. Medical Journal of Australia 2007; 186(12):S77-S108.
25
National Health and Medical Research Council (NHMRC). General Guidelines for Medical
Practitioners on Providing Information to Patients. 2003. Canberra.
26
Hack TF, Degner LF, Watson P, Sinha L. Do patients benefit from participating in medical
decision making? Longitudinal follow-up of women with breast cancer. Psychooncology 2006;
15(1):9-19.
27
Butow PN, Tattersall M. Shared decision-making in cancer care. Clinical Psychologist 2005;
9:54-58.
28
McNutt RA. Shared medical decision making: problems, process, progress. JAMA 2004;
292(20):2516-2518.
Approach to the patient
19
29
Pierce PF, Hicks FD. Patient decision-making behavior: an emerging paradigm for nursing
science. Nurs Res 2001; 50(5):267-274.
30
Charles C, Gafni A, Whelan T. Shared decision-making in the medical encounter: what does it
mean? (or it takes at least two to tango). Soc Sci Med 1997; 44(5):681-692.
31
Charles C, Whelan T, Gafni A. What do we mean by partnership in making decisions about
treatment? BMJ 1999; 319(7212):780-782.
32
Towle A, Godolphin W. Framework for teaching and learning informed shared decision
making. BMJ 1999; 319(7212):766-771.
33
Boakes C, Meyers C. Brain tumor rehabilitation: survey of clinical practice. Archives of
Physical Medicine & Rehabilitation 1993; 74:1247.
34
Taphoorn MJ, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol
2004; 3(3):159-168.
35
Stewart C. The Australian experience of advance directives and possible future directions.
Australasian Journal on Ageing 2005; 24:S25-S29.
36
Taylor D, Tan L. Advance directive knowledge and research appears lacking in Australia.
Emergency Medicine 2007; 12:255-256.
37
National Breast Cancer Centre (NBCC). Clinical practice guidelines for the management of
early breast cancer. 2001. Canberra, National Health and Medical Research Council
(NHMRC).
38
Johnston M, Voegele C. Benefits of psychological preparation for surgery: a meta-analysis.
Annals of Behavioural Medicine 1993; 15:245-256.
39
Burish TG, Snyder SL, Jenkins RA, et al. Preparing patients for cancer chemotherapy: effect of
coping preparation and relaxation interventions. J Consult Clin Psychol 1991; 59(4):518-525.
40
Burton MV, Parker RW, Farrell A, et al. A randomised controlled trial of preoperative
psychological preparation for mastectomy. Psycho-oncology 1995; 4:4-19.
41
Wallace LM. Communication variables in the design of pre-surgical preparatory information.
Br J Clin Psychol 1986; 25 ( Pt 2):111-118.
42
Kaplan RM, Metzger G, Jablecki C. Brief cognitive and relaxation training increases tolerance
for a painful clinical electromyographic examination. Psychosom Med 1983; 45(2):155-162.
43
Devine EC, Westlake SK. The effects of psychoeducational care provided to adults with cancer:
meta-analysis of 116 studies. Oncol Nurs Forum 1995; 22(9):1369-1381.
44
Devine EC, Westlake SK. The effects of psychoeducational care provided to adults with cancer:
meta-analysis of 116 studies. Oncol Nurs Forum 1995; 22(9):1369-1381.
45
Jenkins V, Fallowfield L. Can communication skills training alter physicians' beliefs and
behavior in clinics? J Clin Oncol 2002; 20(3):765-769.
20
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
3
3.1
CLINICAL TRIALS AND RESEARCH
Background
A clinical trial is a study �that involves the administration of a test regimen to humans to evaluate its
efficacy and safety. The term is subject to wide variation in usage, from the first use in humans
without any control treatment to a rigorously designed and executed experiment involving test and
control treatments and randomisation’.1 Clinical trials are the foundation of most improvements in
cancer therapies, including treatment of brain tumours. Clinical trials are usually the result of years of
scientific investigation in the laboratory and in animal models. Treatments that appear promising must
then be tested in clinical trials on patients to determine how the treatment should be given, the safety
and side effects of the treatment, and how effective it is in people with a given condition.
3.1.1
Phase I, II, and III clinical trials
Clinical drug trials take place at different stages in the development of a potentially useful treatment.
Phase I, II and III trials have different designs and may be suitable for different patient populations.
Phase I trials are the first studies in patients that are done to find out how the drug should be given,
how often, and what dose is safe. Few phase I studies are done in Australia in patients with gliomas.
Small numbers of patients are required for most phase I studies, which are usually done in a single
centre.
Phase II trials continue to test the safety and toxicity of a drug or combination but also begin to
evaluate how well the drug works in the disease and setting of interest. Phase II studies usually focus
on a particular type of cancer, and in general all patients receive the same treatment under evaluation.
Phase III trials test a new drug, combination, or surgical or radiation treatment against an accepted
standard treatment. These studies can tell us how a new treatment compares with a standard treatment
in terms of efficacy, safety and side effects. Phase III trials are randomised, in other words, neither the
patient nor the doctor can choose which treatment the patient receives. This is to ensure that the
patients in all treatment groups are similar to each other. Phase III trials in cancer are usually not
blinded, in other words, both the patient and the doctor know which treatment the patient is receiving.
This is usually because it is difficult to blind treatments that are given in very different forms or
schedules, and have different side-effect profiles. Sometimes there is no accepted standard treatment
for the cancer, and patients are randomly allocated to the new treatment in comparison with �best
supportive care’ or placebo.
Phase IV trials are usually trials run after a new treatment is proven to be effective and approved for
use. Such trials may allow patients to access a new treatment that is not widely available due to cost
or one that is not available on the Pharmaceutical Benefits Scheme (PBS). Such trials collect further
information about safety and rare toxicities of new drugs and allow clinicians to become familiar with
the use of a new treatment in a controlled situation.
3.1.2
Why clinical trials are important
Clinical trials are important because only proper, rigorous scientific testing can establish whether a
new treatment is better than the best available standards. Recent advances in brain tumour treatments
have been made after analysis of large and well-conducted clinical trials, including the
recommendation to use combined radiotherapy and chemotherapy and adjuvant chemotherapy with
temozolomide in initial treatment of patients with glioblastoma multiforme2 and the demonstration
that surgery with implantation of carmustine (BCNU) impregnated wafers is superior to surgery alone
in treatment of glioblastoma multiforme.3 Such trials have led to Therapeutic Goods Administration
(TGA) approval and Pharmaceutical Benefits Scheme (PBS) listing of new treatments for brain
tumours in Australia. Areas where randomised clinical trials have never been done remain open to
Clinical trials and research
21
controversy, for example, there is no unequivocal evidence that gross total resection of high-grade
gliomas is better than partial tumour debulking or biopsy alone.
3.1.3
Conduct of clinical trials in patients with brain tumours
In Australia, clinical trials in patients with brain tumours may be conducted by several mechanisms.
•
Pharmaceutical companies. Pharmaceutical companies that develop new drugs must complete
•
Cooperative groups. Cooperative groups are groups of clinicians and researchers interested in
•
Single institutions and consortia. Some investigator-initiated studies are done at a few hospitals or
phase I, II and III trials before they can market their product. Many clinical trials of new
treatments for brain tumours are sponsored by pharmaceutical companies. A prominent expert in
the area is often chosen to be the Principal Investigator and is involved in developing the trial
protocol. Participating clinicians may also contribute to protocol development. Such trials usually
have a sound scientific rationale and are well designed and rigorously conducted.
specific diseases. Cooperative oncology groups in Australia with a special interest in brain
tumours include the Trans Tasman Radiation Oncology Group (TROG) and the Cooperative
Trials Group for Neuro-Oncology (COGNO). These groups may obtain funding from competitive
Federal or State grants to run a trial to answer an important clinical question. Pharmaceutical
companies sometimes provide financial support or drugs for such trials. Most cooperative group
trials are investigator-initiated, that is they are conceived and initiated by specialist doctors at one
or more institutions.
units.
3.1.4
Ethical review and governance of clinical trials in brain tumours
Before patients can be enrolled onto a clinical trial in Australia, the trial must be reviewed by other
expert clinicians and researchers to ensure that it is scientifically well designed and will be able to
answer the study question. It will also have been reviewed by at least one Human Research Ethics
Committee (HREC) to ensure that the trial protocol adheres to guidelines for clinical trial conduct as
laid out in the NHMRC National Statement on Ethical Conduct in Human Research (2007).4 The
HREC is also required to evaluate the scientific merit as part of the ethical review unless it has
already been done elsewhere and it should ensure that no member of the trial team has an undisclosed
conflict of interest.
3.1.5
Patient participation in clinical trials for brain tumours in Australia
In a recent review of 828 patients from the Victorian Cancer Registry with gliomas, 39 patients (5%)
were enrolled on a clinical trial during their illness.5 The National Cancer Research Network in the
United Kingdom set a target in 2000 of doubling participation in clinical trials for all cancer patients,
and reached that target in 2004, with 10.9% of all patients being enrolled in a clinical trial.6 However,
this remains a small proportion of all cancer patients. There are no specific guidelines for clinical trial
enrolment targets for patients with brain tumours in Australia or elsewhere. However, ideally, all
patients should have access to treatment in a centre where clinical trials are offered. It is recognised
that in Australia the distance of some patients from a tertiary referral centre will be a barrier to access
and participation in clinical trials. Elderly patients are under-represented in clinical trials, and patients
who are otherwise eligible should not be excluded solely on the basis of advanced age. Enrolment in
studies of less common brain tumours such as anaplastic astrocytomas and oligodendrogliomas should
be encouraged but it may be necessary to collaborate internationally to accrue sufficient numbers for a
meaningful study.
22
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
3.1.6
Special issues surrounding clinical trials for brain tumour patients
The requirement for obtaining informed consent is a core principle of clinical trial participation. This
requirement is more difficult when patients suffer cognitive impairment, impairment of judgment, and
receptive dysphasia. Nevertheless, the National Statement states that people with cognitive
impairment are entitled to participate in research.4
The National Statement4 provides guidance for recruiting patients with a cognitive impairment that
includes consent being given by a person with lawful authority to decide for that participant (see
Chapter 2 Approach to the patient; Chapter 12 Psychosocial Care.) It is important to note that the
law, and therefore the mechanism, by which a person may perform the role of �guardian’ for the
person unable to give consent differs in each Australian jurisdiction. For this reason it is important to
become familiar with the local and Federal legislative regulations and establish whether a person has
authority to give a lawful consent on behalf of another. In some jurisdictions (for example, Western
Australia) the law does not include consent being given for participation in research, only for
treatments that may be in the best interest of the patient. In certain circumstances then the physician’s
judgment that enrolment in a trial is consistent with treatment likely to be in the patient’s best interests
may be sufficient justification for lawful enrolment. In these instances the senior next of kin or person
responsible should be identified and informed of the decision and the reasons for it.
A minority of patients may have a physical disability that renders them unable to sign a consent form
despite intact cognition (eg dominant hemisphere involvement and hemiparesis). Such patients should
not be excluded from clinical trials if they are otherwise eligible. Alternatives may include verbal
consent witnessed by an independent third party, or an individual authorised under relevant
Guardianship legislation may sign the consent form.
3.1.7
Design of valid and meaningful clinical trials in brain tumours in
Australia
Investigators should pay attention to general principles of clinical trial design and reporting such as
those set out in the Consolidated Standards of Reporting Trials (CONSORT) statement.7 However,
some important points are more specific to clinical trials in brain tumours.
3.1.8
Recommended stratification variables for brain tumour trials
Stratification for known important prognostic factors should be used:8,9
•
age
•
Karnofsky or ECOG performance status
•
biopsy only versus gross total resection or debulking
•
histology
Factors may be grouped using recursive partitioning analysis to identify distinct prognostic groups.10
In addition, genetic markers of prognosis (eg 1p19q loss of heterozygosity) are becoming more
important and stratification for these variables should be considered.11
Central pathological review
Central pathology review by a specialist neuro-pathologist should be performed whenever possible in
clinical trials in brain tumours. Identification of oligodendroglial components is particularly important
in view of the increased sensitivity of these components to chemotherapy12 (see Chapter 9
Oligodendroglioma). Inter-observer variability is particularly marked for intermediate-grade tumours
such as anaplastic astrocytomas, with concordance rates as low as 36% in some series.13 Confirmation
of tumour grade is particularly important where survival or progression are endpoints.14
Clinical trials and research
23
Central radiological review
Central radiological review by a specialist neuro-radiologist should be performed wherever possible
in clinical trials with glial tumours due to the high degree of inter-observer variability in assessment
of response.15
Ideal trial management committee structure
Trial design should be overseen by expert clinical trialists. A multidisciplinary trial management
committee is recommended for all brain tumour clinical trials. Suggested participants include:
•
neurosurgeon
•
radiation oncologist
•
medical oncologist
•
biostatistician
•
neuroradiologist
•
consumer
•
consider nurse researcher
•
consider health-related quality of life (HRQL) researcher
•
consider neurocognitive function researcher
•
consider neuropathologist
A quality assurance committee should be established to monitor adherence to the trial protocol so that
treatments are standardised between centres.
3.1.9
Recommended study endpoints for brain tumour clinical trials
Overall survival
Overall survival is the most reliable and preferred endpoint for phase III studies in many tumour
types. However, there is some concern that overall survival may not always reflect patient benefit in
neuro-oncology, with functional and cognitive status being particularly important due to their frequent
impairment in this population.16
Time to progression
Time to progression (TTP) must be defined strictly in the clinical trial protocol, as there is no standard
definition. This endpoint usually reflects the time from enrolment until progression as defined on
imaging criteria (which may be study-specific) or death, but may also include neurological
deterioration without change on imaging. The reported phenomenon of �pseudo-progression’, or a
radiological appearance consistent with progression that subsequently improves spontaneously, makes
TTP a less reliable endpoint than overall survival.17
Six-month progression-free survival
Six-month progression-free survival (PFS) is becoming widely used as an endpoint in brain tumour
clinical trials18 although there are no available published data on the use of this endpoint. Important
points to consider for use of six-month PFS as an endpoint include:
•
24
a requirement to standardise frequency of radiologic evaluation
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
•
consideration of use of both neurological and radiological progression as events
•
ensuring that only patients with documented disease progression are eligible to enter the clinical
trial.
•
blinding of reviewers to the intervention allocation group
•
the phenomenon of �pseudo-progression’ may make six-month PFS more unreliable as a surrogate
endpoint than overall survival.
Radiological objective response
Standardised response criteria are not well developed for brain tumours, and objective tumour
response rates correlate poorly with survival in clinical trials.19 Usual practice is to measure the area
of gadolinium enhancing tumour on MRI; however changes in gadolinium enhancement may reflect
alterations in vascular permeability and architecture as well as decrease in tumour volume. The more
recent uni-dimensional RECIST criteria that were developed with reference to CT scanning in other
solid tumours, do not provide specific guidelines for measurement in brain tumours, and have not
been well validated in this group, with comparison between WHO and RECIST responses in 30
patients only.20,21 The bi-dimensional �Macdonald criteria’ were developed in 1990 as an attempt to
address the shortcomings of the WHO criteria for assessment of response in brain tumours.22
However, these guidelines are based on expert opinion and did not attempt to correlate response with
survival or patient benefit. Subsequent investigators have attempted to address this issue, showing that
for high-grade gliomas there is good correlation between one-dimensional (RECIST), twodimensional and volumetric measurements. However, the observation of response using these
measurements does not predict survival well; time to progression may be a better surrogate for
survival than objective response.23 For non-enhancing tumours, no imaging or response parameters
predict survival.
Imaging characteristics may be altered by changes in corticosteroid doses, radiotherapy, implantable
chemotherapy wafers, and radiosurgery. Newer agents such as angiogenesis inhibitors also can affect
vascular permeability and the appearance of neuro-imaging. Particular attention should be paid to
recording corticosteroid dose at the time of imaging, a strength of the Macdonald criteria. Patients
should be maintained on a stable corticosteroid dose at baseline imaging and a partial response should
not be recorded where the corticosteroid dose has increased from baseline.
Health-related quality of life
The inclusion of HRQL endpoints in brain tumour clinical trials is important due to the progressive
cognitive and physical decline experienced by these patients, and the potential for treatments such as
surgery, radiotherapy and chemotherapy to adversely affect HRQL. However, collection of HRQL
data may be challenging and concurrent use of corroborative proxy HRQL data should be
considered.24
Validated tools for measurement of HRQL are available for use in patients with brain tumours. Such
tools include the Functional Assessment of Cancer Therapy-General (FACT-G) and brain module
(FACT_Br)25 and the European Organisation for the Research and Treatment of Cancer Quality of
Life Questionnaire–core questionnaire (EORTC QLQ-C30) and brain cancer module (BCM-20).26
Patients with high-grade gliomas and good performance status (such as those enrolled on clinical
trials) can comply with the requirements of HRQL collection.27
Cognitive function
Measures of cognitive function are important and should be included in randomised clinical trials,
however the best tools to use for measurement are unclear and there is no accepted �gold
standard’.28,29 Neurocognitive deterioration may precede progression on imaging30 and is also a strong
independent predictor of survival31. Simple tests such as the Mini Mental State Examination are
Clinical trials and research
25
insensitive in this population.29 The role of cognitive function endpoints in earlier phase trials is
unclear. Measurement of neurocognitive functioning and resourcing for this aspect of a clinical trial
are challenging for investigators. Both progression of disease and treatments (surgery, radiotherapy)
may lead to deterioration in cognitive function.
Correlative studies in clinical trials in patients with brain tumours
Consideration should be given to tissue collection and bio-banking for future molecular profiling in
clinical trials in patients with gliomas at diagnosis and recurrence. Autopsy studies may provide
additional information.
Key points for astrocytomas and oligodendrogliomas:
•
Eligible patients should be offered clinical trial participation or referred to a centre where
clinical trial participation is available.
•
The ethical principles of written informed consent should be carefully considered in
patients with cognitive impairment, receptive dysphasia, or impairment of judgment.
•
Multidisciplinary involvement in a trial management committee is recommended for
clinical trials in gliomas.
•
The use of several corroborative endpoints such as six-month progression-free survival,
radiological response, cognitive function, and health-related quality of life are
recommended for clinical trials in gliomas, however overall survival is the most robust
endpoint.
•
Validated tools should be used for measurement of neurocognitive function and healthrelated quality of life.
•
Clinical trials in glioma should include central review of histopathology and radiological
endpoints.
•
Consideration should be given to collection of tissue for biobanking and at autopsy in
clinical trials.
Recommendations
Level
References
Time to progression is a better surrogate for survival than objective
radiological response and should be incorporated as an
endpoint in clinical trials.
III
23
Patients in clinical trials should be stratified for known important
prognostic factors.
III
9
Central specialised neuro-pathology review must be
incorporated into therapeutic clinical trials in brain tumours.
II
14
Validated health-related quality of life (HRQL) tools are available
and should be used where measurement of HRQL is planned.
III
25,26
References
1
26
Last J.M.ed. A Dictionary of Epidemiology. 4th ed. Oxford: Oxford University Press, 2001.
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
2
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al. Radiotherapy
plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;
352(10):987–996.
3
Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC et al. A phase 3 trial of
local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in
patients with primary malignant glioma. Neuro Oncol 2003; 5(2):79–88.
4
National Health and Medical Research Centre. Statement on Ethical Conduct in Research
Involving Humans. 2007. Canberra.
5
Rosenthal MA, Drummond KJ, Dally M, Murphy M, Cher L, Ashley D et al. Management of
glioma in Victoria (1998–2000): retrospective cohort study. Medical Journal of Australia
184(6):270–3, 2006.
6
National Cancer Research Network (NCRN). National Cancer Research Network Annual
Report 2003–2004. 2004.
7
Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I et al. Improving the quality of
reporting of randomized controlled trials. The CONSORT statement. JAMA 276(8):637–9,
1996.
8
Curran WJ, Jr., Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ et al. Recursive
partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group
malignant glioma trials. Journal of the National Cancer Institute 85(9):704–10, 1993.
9
Shaw EG, Wisoff JH. Prospective clinical trials of intracranial low-grade glioma in adults and
children. Neuro-oncol 2003; 5(3):153–160.
10
Lamborn KR, Chang SM, Prados MD. Prognostic factors for survival of patients with
glioblastoma: recursive partitioning analysis. Neuro Oncol 2004; 6(3):227–235.
11
Brandes AA, Tosoni A, Cavallo G, Reni M, Franceschi E, Bonaldi L et al. Correlations
between O6-methylguanine DNA methyltransferase promoter methylation status, 1p and 19q
deletions, and response to temozolomide in anaplastic and recurrent oligodendroglioma: a
prospective GICNO study. J Clin Oncol 2006; 24(29):4746–4753.
12
Donahue B, Scott CB, Nelson JS, Rotman M, Murray KJ, Nelson DF et al. Influence of an
oligodendroglial component on the survival of patients with anaplastic astrocytomas: a report
of Radiation Therapy Oncology Group 83-02. International Journal of Radiation Oncology,
Biology, Physics 38(5):911–4, 1997.
13
Mittler MA, Walters BC, Stopa EG. Observer reliability in histological grading of
astrocytoma stereotactic biopsies. Journal of Neurosurgery 85(6):1091–4, 1996.
14
Kraus JA, Wenghoefer M, Schmidt MC, von Deimling A, Berweiler U, Roggendorf W et al.
Long-term survival of glioblastoma multiforme: importance of histopathological reevaluation.
Journal of Neurology 247(6):455–60, 2000.
15
Vos MJ, Uitdehaag BM, Barkhof F, Heimans JJ, Baayen HC, Boogerd W et al. Interobserver
variability in the radiological assessment of response to chemotherapy in glioma. Neurology
60(5):826–30, 2003.
16
Thoughtful assessment. Lancet Oncology 7(3):189, 2006.
Clinical trials and research
27
17
Mason WP, Maestro RD, Eisenstat D, Forsyth P, Fulton D, Laperriere N et al. Canadian
recommendations for the treatment of glioblastoma multiforme. Curr Oncol 2007; 14(3):110–
117.
18
Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM et al.
Progression-free survival: an important end point in evaluating therapy for recurrent highgrade gliomas. Neuro Oncol 2008; 10(2):162–170.
19
Brada M, Sharpe G. Chemotherapy of high-grade gliomas: beginning of a new era or the end
of the old? European Journal of Cancer 32A(13):2193–4, 1996.
20
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al. New
guidelines to evaluate the response to treatment in solid tumors. European Organization for
Research and Treatment of Cancer, National Cancer Institute of the United States, National
Cancer Institute of Canada. Journal of the National Cancer Institute 92(3):205–16, 2000.
21
Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a review of validation studies on
tumour assessment. European Journal of Cancer 42(8):1031–9, 2006.
22
Macdonald DR, Kiebert G, Prados M, Yung A, Olson J. Benefit of temozolomide compared
to procarbazine in treatment of glioblastoma multiforme at first relapse: effect on neurological
functioning, performance status, and health related quality of life. Cancer Investigation
23(2):138–44, 2005.
23
Galanis E, Buckner JC, Maurer MJ, Sykora R, Castillo R, Ballman KV et al. Validation of
neuroradiologic response assessment in gliomas: measurement by RECIST, two-dimensional,
computer-assisted tumor area, and computer-assisted tumor volume methods. NeuroOncology 8(2):156–65, 2006.
24
Hahn CA, Dunn RH, Logue PE, King JH, Edwards CL, Halperin EC. Prospective study of
neuropsychologic testing and quality-of-life assessment of adults with primary malignant
brain tumors. International Journal of Radiation Oncology, Biology, Physics 55(4):992–9,
2003.
25
Weitzner MA, Meyers CA, Gelke CK, Byrne KS, Cella DF, Levin VA. The Functional
Assessment of Cancer Therapy (FACT) scale. Development of a brain subscale and
revalidation of the general version (FACT-G) in patients with primary brain tumors. Cancer
75(5):1151–61, 1995.
26
Osoba D, Aaronson NK, Muller M, Sneeuw K, Hsu MA, Yung WK et al. The development
and psychometric validation of a brain cancer quality-of-life questionnaire for use in
combination with general cancer-specific questionnaires. Quality of Life Research 5(1):139–
50, 1996.
27
Osoba D, Aaronson NK, Muller M, Sneeuw K, Hsu MA, Yung WK et al. Effect of
neurological dysfunction on health-related quality of life in patients with high-grade glioma.
Journal of Neuro-Oncology 34(3):263–78, 1997.
28
Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of
patients with CNS tumors. Journal of Clinical Oncology 24(8):1305–9, 2006.
29
Meyers CA, Wefel JS. The use of the mini-mental state examination to assess cognitive
functioning in cancer trials: no ifs, ands, buts, or sensitivity. Journal of Clinical Oncology
21(19):3557–8, 2003.
28
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
30
Meyers CA, Hess KR. Multifaceted end points in brain tumor clinical trials: cognitive
deterioration precedes MRI progression. Neuro-Oncology 5(2):89–95, 2003.
31
Meyers CA, Hess KR, Yung WK, Levin VA. Cognitive function as a predictor of survival in
patients with recurrent malignant glioma. Journal of Clinical Oncology 18(3):646–50, 2000.
Clinical trials and research
29
4
CLINICAL PRESENTATION
The presenting symptoms of gliomas are determined by several factors including the tumour’s size,
location and rate of growth. A small tumour deep in the dominant hemisphere may produce
significant neurological deficits whereas a tumour in the non-dominant frontal lobe may reach a very
large size before becoming symptomatic. A low-grade glioma grows slowly as an infiltrating tumour
but a glioblastoma multiforme is an aggressive tumour that in general grows rapidly as a mass.
Although a glioblastoma multiforme may arise de novo, it may develop from a lower-grade glioma
that has dedifferentiated. A more rapidly growing tumour is more likely to create symptoms of raised
intracranial pressure than one that grows more slowly.
Gliomas may present with symptoms of raised intracranial pressure or with focal neurological
symptoms that reflect the location of the tumour within the brain. Patients commonly have more than
one symptom at presentation. After the initial presentation, family members or friends may report
other symptoms that in retrospect they have noticed in the preceding weeks or months prior to the
diagnosis, such as subtle cognitive changes. Patients with multi-focal gliomas may have symptoms
and signs arising from more than one area of the brain. Low-grade gliomas and high-grade gliomas
have different patterns of presentation; in particular, the incidence of seizures differs between tumour
types (see Table 4.1).
Proportion of cases presenting with specific symptoms1–8
Table 4.1
Presenting symptom
Low-grade glioma (%)
Glioblastoma multiforme (%)
Headache/signs of increased
intracranial pressure
5–53
19–34
Hemiparesis
20–26
14–41
Seizure
78–89
17–31
Cognitive deficits
11–39
15–22
Speech deficit/aphasia
*
6–32
Visual disturbance
*
3–15
Ataxia
*
9
Cranial nerve dysfunction
*
9
Dizziness
*
9
Loss of consciousness
*
4
Focal neurological deficits
31
*
Transient events
5
*
* prevalence unknown
4.1
Symptoms of raised intracranial pressure
4.1.1
Headache
There have been numerous studies addressing the nature of headaches in patients with brain tumours
but there are no studies that have examined headaches only in patients with gliomas. These studies
have included patients with different types of primary brain tumours, as well as patients with brain
metastases but they are still relevant as they are essentially examining the types of headaches that are
produced by a tumour mass in the brain. The one caveat is that the incidence of posterior fossa
tumours in these studies is greater than usually occurs in adult patients with gliomas. More modern
30
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
studies have the advantage over older studies of improved neuro-imaging techniques (see Chapter 5
Imaging).
The classical description of a brain tumour headache9,10 is one that starts in the early morning and
disappears soon after the patient gets up. It is initially mild but then becomes progressively more
severe, frequent and of longer duration, and eventually becomes almost constant. It is typically worse
with the Valsalva manoeuvre, and is associated with nausea and vomiting. More recent studies
however have shown that this type of headache occurs in only a small proportion (17%) of patients.11
Headache characteristics
Forsyth and Posner11 demonstrated that the commonest headache type was a tension-type headache
(77% of patients). Nine percent had a migraine-like headache, and 14% had a mixture of headaches
that could not be easily classified. The tension-type headaches were described as a dull ache, pressure
or like a sinus headache, usually bifrontal but worse on the side of the tumour. The patients with
migraine-like headaches all had atypical features, and all had other neurological symptoms or signs.
Suwanwela et al12 also showed that in most patients (74%) the headache was dull and aching, and
throbbing in 26%. Rushton13 found that 58% of patients had constant headaches, and 14% had
throbbing headaches; some patients had mixed types of headaches, and in others they were unable to
classify the headaches due to inadequate information. By contrast, Pfund14 found that only 16% of
139 patients with brain tumours had tension-type headaches and 7% had migraine-like headaches, and
that the headaches were throbbing in 63%, and shooting in 38%.
Timing of the headache
Forsyth11 found that the headache was worse in the morning in 36% of patients, worse at night in
17%, worse during the day in 13%, and in 34% there was no clear variation in headache intensity
during the course of the day. Rushton13 found that 25% occurred during sleep or arising, 43%
occurred at any time, 2% occurred in the afternoon or evening, and in 30% the time of onset could not
be determined. Suwanwela12 found that 18% had early morning headache, 20% had headache upon
arising, and 71% had nocturnal headache. Pfund14 found that headache occurred upon rising in 14%,
in the morning in 32%, nocturnally in 27%, and were variable in 27%. It can be concluded that there
is no typical daily rhythm to brain tumour headaches.
Constancy of the headache
Brain tumour headaches are intermittent in 62–88% of patients.11–14 Pfund14 found that the headache
occurred daily in only 11% of patients, but it was progressive in 79%.
Aggravating factors
The headache can be worse with bending over in 18–32%11,13. Suwanwela12 found that a change in
body position, especially arising from bed, aggravated or brought on the headache in 20%. Headaches
worsened with the Valsalva manoeuvre in 18–30%.11–13
Nausea and vomiting
Nausea or vomiting is present in 36–60% of patients.11–14
Severity of headache
The headache is moderate to severe in most patients, but in some (10–20%) was only mild.11–14 In
Forsyth’s study11 headache was the worst symptom in 45% of patients.
Effectiveness of simple analgesics
Simple analgesics are effective in moderately to completely relieving the headaches in 30–58% of
patients.11–13
Clinical presentation
31
Site of the headache
Forsyth11 found that the commonest headache site was the frontal region (68%), seen primarily in
supratentorial tumours or in patient with raised intracranial pressure. They could not reliably
differentiate supra- and infratentorial tumours based on headache location, although infratentorial
tumours usually had increased intracranial pressure. Pfund14 showed that 73% of patients with
infratentorial tumours had frontal, temporal or parietal headaches, and 24% had nuchal and occipital
headaches. In most patients the site of the headache does not assist in localising the tumour.
Localisation of the tumour based on the site of the headache is best in those patients who do not have
evidence of raised intracranial pressure. Headaches are unilateral in 25–30%11,12, and they are
ipsilateral to the tumour particularly if there is no raised intracranial pressure. Headaches are more
common with infratentorial than with supratentorial tumours.12,14
History of prior headaches
Forsyth11 found that patients who had a history of prior headache were more likely to have headaches
with a brain tumour. In 36% the brain tumour headache was identical to their previous headache, but
was more severe, more frequent, or associated with other symptoms or signs, suggesting either a focal
lesion or raised intracranial pressure. Rushton13 found that 18 of the 132 brain tumour headache
patients they studied had a past history of headache that in recent months had changed character and
was associated with the development of other symptoms due to their tumour.
Headache as an isolated symptom
In a prospective study Vasquez-Barquero15 found that only 15 of the183 patients (8%) with
intracranial tumours had headache as their first and only symptom; by the time of tumour diagnosis,
only one of these 15 still had only headache at the time of diagnosis. In Forsyth’s study11, only 57% of
patients had neuro-imaging primarily because of headaches.
Cause of brain tumour headache
Brain tumour headache is related to the size of the tumour and amount of midline shift, which
produces traction on pain-sensitive structures such as blood vessels, dura and certain cranial
nerves.9,11,16 Obstruction of CSF pathways may lead to hydrocephalus which may also cause
headache.
Neuro-imaging for patients with headaches
In patients with a past history of headache, neuro-imaging should be performed if there is a change in
character or pattern of the headache, or if there is the development of focal neurological symptoms
and signs. A patient with new onset or recurrent headache uncharacteristic for that patient should also
be imaged, particularly if there are focal neurological symptoms and signs.11,13,14,17
Recommendation
Level
References
A patient with new onset or recurrent headache uncharacteristic
for that patient should also be imaged, particularly if there are
focal neurological symptoms and signs.
III
11,13,14,17
Plateau waves
Plateau waves are paroxysmal episodes of neurological dysfunction caused by a sudden rise in
intracranial pressure.18 They may occur spontaneously or be precipitated by the Valsalva manoeuvre
or by standing up, particularly in the morning.19 Episodes last between five and 20 minutes. The
commonest symptoms are headache, restlessness, altered consciousness, and sudden weakness of the
legs with collapse and without loss of consciousness. Other symptoms include confusion, blurred
32
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
vision, ophthalmoplegia, clonic movements of the limbs and urinary incontinence.18 Plateau waves are
due to an increase in cerebral blood volume that is due to a sudden decrease in cerebral vascular
resistance.20,21 They may be mistaken for seizures or transient ischaemic attacks. They may lead to
cerebral herniation, respiratory arrest and death.
4.2
Focal neurological symptoms
4.2.1
Brain tumours and cognition
Likelihood of a brain tumour presenting with cognitive deficits
Cognitive deficits in patients with brain tumours can be caused by the tumour itself; by tumour-related
epilepsy; by the treatment of the tumour and its effects (surgery, radiotherapy, anti-epileptics,
chemotherapy, or corticosteroids); or by psychological distress.22 More likely, a combination of these
factors will contribute to cognitive dysfunction.
Patients with brain tumours can present with cognitive complaints and deficits. Although presentation
with cognitive deficits alone is uncommon, subtle cognitive dysfunction is often found in patients
with rapidly growing, high-grade tumours. Tucha et al studied the incidence of cognitive impairment
among patients with brain tumours, immediately after diagnosis but before the commencement of
treatment, by performing a battery of neuropsychological tests on 139 patients.23 They found that 91%
of 126 patients displayed significant impairments in at least one area of cognition. For 71% of the
patients, neuropsychological assessments revealed impairments in three or more areas of mental
performance. For one third of the patients, impaired functioning in eight or more cognitive areas was
observed. Results from other studies in patients with high-grade glioma also indicate that the tumour
itself is an important contributor to cognitive deficits.24 Klein et al. assessed cognition in 68 newly
diagnosed patients with high-grade glioma and found all exhibited signs of cognitive impairment.
These deficits could at least be partly explained by impaired visual and motor functions.
Cognitive deficits and tumour progression
Cognitive deficits may also be caused by recurrent tumour and assessments of cognition have been
shown to be a valid method of monitoring for tumour progression. A study of 56 patients with tumour
progression found that cognitive deterioration occurred six weeks prior to radiographic failure on MRI
whereas reports of deterioration in quality of life and activities of daily living occurred after
radiographic progression.25
Cognitive deficits and tumour histology
The relationship between tumour histology and cognitive dysfunction has been studied but no clear
correlation has been identified. An early study reported that the profiles of the patients with the
highest grades of malignant cerebral tumours (anaplastic astrocytomas (AA), glioblastoma multiforme
(GBM), and metastatic carcinoma) demonstrated greater cognitive impairments that patients with
more slowly growing tumours (astrocytoma grade I and II, ependymoma, oligodendroglioma, or
tuberculoma).26 In this study however, the two groups were not aged matched, the higher-grade
tumour group being significantly older that the low-grade tumour group. Also, no estimates of tumour
size (area) or volume were presented. Kayl et al compared the neuropsychological functioning of 24
patients with GBM and 24 patients with anaplastic astrocytoma.27 The groups were matched for age,
gender, education as well as tumour location and tumour volume. Analysis of co-variance as well as
multiple regression and correlation analyses failed to find any relationship between tumour type,
tumour volume and neuropsychological test scores. The authors concluded that tumour histology is
not clearly predictive of cognitive performance in adults with GBM and AA.
Likelihood of a brain tumour being the cause of dementia
A retrospective study from a tertiary care memory clinic assessed the prevalence of potentially
reversible dementias and whether the cognitive dysfunction improved or resolved after treatment.28 Of
Clinical presentation
33
196 cases that presented with definite or suspected dementia 45 (23%) were found to have a
potentially reversible cause. Of these, only two cases (1%) were found to be due to brain tumour.
Clarfield undertook a meta-analysis of 32 studies involving 2889 subjects that investigated the
prevalence of various causes of dementia.29 Particular attention was paid to potential and actual
reversibility. Of the 2889 cases of dementia, 42 (1.5%) were found to be due to cerebral tumours.
Only 11 of the 32 studies provided adequate details of follow-up to assess reversibility. Eleven
percent of cases of dementia reversed in part (8%) or fully (3%). Of the 11% of cases that reversed,
only 4% (n = 4) were attributed to brain tumour.
4.2.2
Seizures
Likelihood of seizures in a patient with a brain tumour
The overall incidence of seizures in patients with brain tumours is up to 35%.30 The most common
pathologies in patients with recurrent seizures and brain tumours are ganglioglioma and low-grade
astrocytoma. Significantly less common are oligodendroglioma, mixed glioma and dysembryoplastic
neuroepithelial tumour (DNET).31–33 A study from the Cleveland Clinic in patients with seizures as
the only symptom of primary brain tumour found ganglioglioma in 38%, low-grade astrocytoma in
33%, oligodendroglioma in 10%, low-grade glioma in 5%, and 5% were DNET.33 In a different series
of patients with epilepsy and a low-grade cerebral tumour, ganglioglioma was the most frequent
pathology (45%), and seizures in this group commenced at a younger age than patients with other
low-grade tumours.34
The likelihood of a patient with a primary cerebral tumour experiencing recurrent seizures relates to
tumour histology. Although still unexplained, various tumour types have different epileptogenic
potential. Studies suggest that patients with cerebral tumours presenting with seizures were more
likely to have a low-grade tumour and a normal examination.30 In a review at the Montreal
Neurological Institute, the highest seizure incidence was for patients with oligodendroglioma (92%),
astrocytoma and meningioma had a seizure incidence of approximately 70%, and there was a 35%
seizure incidence in patients with glioblastoma. This finding has been borne out by other studies.35
Although uncommon as a tumour type, ganglioglioma is associated with recurrent seizures in almost
all patients.36 Patients with seizures were also more likely to have a cortical tumour location.37
The natural history of seizures associated with brain tumours is that of a stable seizure frequency and
long duration of epilepsy at the time of surgery.31,35,38 At presentation these seizures were focal in
40%, and generalised or secondarily generalised in 50%. However in patients with persisting epilepsy,
74% of patients had focal seizures, whereas only 19% had generalised or focal and generalised
seizures. Late onset seizures are uncommon, with only 14% of patients developing seizures after
diagnosis and first tumour treatment.37 Thus in patients without initial seizures, the probability of
developing epilepsy is low.
Likelihood of a brain tumour in patient presenting with seizures
The incidence of brain tumours in patients with medically refractory epilepsy has traditionally been
reported as only 3.5% of patients with epilepsy.39 This figure may be artificially low, however, as this
and many other studies were performed before the advent of MRI. More recent studies have placed
this proportion at 10–15%.33,38,40,41 A Danish study has found the incidence of cerebral tumours in
patients with epilepsy diagnosed after the age of 25 was 16%.42 The incidence rises further when
patients are selected from a centre with an active surgical treatment program for intractable epilepsy,
and is up to 23% in patients with temporal lobe epilepsy.32,35,43 This increase is more likely to reflect
referral patterns rather than an increase in incidence of cerebral tumours per se.
In patients presenting with a first seizure, the incidence of a primary brain tumour ranges from 6% to
12%.44,45 The proportion of cases varies in part depending on referral patterns and patient selection.
Patients presenting with a first seizure should have adequate neuro-imaging with MRI (see Chapter 5
Imaging).
34
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key point:
•
Patients presenting with a first seizure should have adequate neuro-imaging with MRI.
4.2.2
Other focal neurological symptoms
As discussed earlier, brain tumours can present with any focal neurological symptom. Although
patients with brain tumours typically present with a history of symptoms going back days, weeks,
months or even years, in some patients symptoms can come on fairly acutely, and the presentation can
be confused with a cerebral infarct or transient ischaemic attack. All patients who present with focal
neurological symptoms (such as hemiparesis, dysphasia, dysarthria, neglect, hemianopia, dressing
apraxia) require neuro-imaging to establish the cause of these symptoms.
Key point:
•
All patients who present with focal neurological symptoms (such as hemiparesis,
dysphasia, dysarthria, neglect, hemianopia, dressing apraxia) require neuro-imaging to
establish the cause of these symptoms.
Genetics of gliomas
Most gliomas arise as a consequence of acquired somatic mutations of unknown cause in genes
responsible for control of cell growth and proliferation. Most of these genetic alterations result in
disruption of oncogenes, tumour suppressor genes, DNA repair genes and cell death genes and affect
three main cellular systems: RB1, p53 and tyrosine kinase receptor pathways. Other genetic
alterations promote mitotic signal transduction, cell cycle regulation, apoptosis, angiogenesis and cell
invasion. Most gene alterations induce cell-cycle dysfunction at a complex molecular level.46,47
Most anaplastic oligodendrogliomas and oligoastrocytomas have a characteristic genetic alteration
with a deletion of the short arm of chromosome 1 (1p) with or without loss of the long arm of
chromosome 19 (19q). These alterations are associated with superior survival and potentially with an
increased likelihood of response to chemotherapy.48
Inherited genetic syndromes are responsible for a few percent of gliomas.49
4.2.3
Inherited predisposition to gliomas
Neurofibromatosis
Central nervous system tumours seen in neurofibromatosis type 1 (NF1) include optic nerve gliomas
(particularly in children) and other astrocytomas (cerebral or spinal) as well as meningiomas. The
condition is inherited in an autosomal dominant fashion and affects one in 3000 individuals. The NF1
is a very complex tumour suppressor gene that sits on chromosome 17 and codes for the
neurofibromin gene.50 Skin signs include neurofibromas, axillary and groin freckling and cafГ© au lait
(hyper-pigmented) spots. Other characteristic features include Lisch nodules (hamartomas of the iris),
intellectual disability and scoliosis. Many with the condition have subtle features only (skin signs)
while others are more severely affected (intellectual disability or optic glioma /astrocytoma). Those
with neurofibromatosis type 2 classically have bilateral acoustic neuromas (schwannomas) but can
also develop astrocytomas and meningiomas.51
Tuberous sclerosis
Tuberous sclerosis (TS) affects one in 5000–10,000 individuals and classically causes epilepsy and
intellectual disability as well as a variety of skin signs. However the features of the condition are
variable. It is inherited in an autosomal dominant fashion but more than half of cases are new
mutations. Classical skin signs include multiple hypo-pigmented patches, shagreen patches (a
Clinical presentation
35
shagreen patch is an oval-shaped nevoid plaque, skin-coloured or occasionally pigmented, smooth or
crinkled, appearing on the trunk or lower back in early childhood; sometimes seen with other signs of
tuberous sclerosis), adenoma sebaceum and subungual fibromas. CNS features include cortical tubers
and subependymal nodules. Up to 10% of those with TS can develop a subependymal giant cell
astrocytoma.52
Li Fraumeni syndrome (LFS)
This condition is due to a germline mutation in the p53 gene. High-grade gliomas occur in patients
with this condition, which is inherited in an autosomal dominant fashion. Other commonly seen
cancer types include premenopausal breast cancer, bone and soft tissue sarcomas, and acute
leukaemias and paediatric cancers, particularly adrenocortical carcinomas. The condition is highly
penetrant with 90% of those with the condition having a tumour by the age of 70.53
Hereditary colorectal cancer syndromes
Hereditary non-polyposis colorectal cancer (HNPCC) is a hereditary bowel cancer syndrome that is
inherited in an autosomal dominant fashion. Apart from colorectal cancer, which is classically right
sided and occurs at a median age of 45, other tumour types seen include uterine cancer and less
commonly, stomach cancer, ovarian cancer, small intestinal cancer, biliary /pancreatic cancer,
transitional cell carcinoma of the lining of the upper urinary tract (TCC ureter), and high-grade glioma
(the last in 1–2% of cases).
Familial adenomatous polyposis (FAP) is an autosomal dominant condition and can predispose to the
development of primary brain tumours. These are typically medulloblastomas but can be gliomas.54
Turcot syndrome is the association between familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer and brain tumours like medulloblastoma and malignant glioma.55
Hereditary glioma
Rarely, families are described in which two or more first- or second-degree relatives have had highgrade gliomas. The pattern of inheritance is either autosomal recessive or autosomal dominant.56
36
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points:
•
Consider referral of patients with glioma to a clinical genetics service if the patient or their
first- or second-degree relatives have features or family history suggestive of
neurofibromatosis type 1 or tuberous sclerosis.
•
Consider referral of patients with high-grade gliomas to a Cancer Genetics
Service/Familial Cancer Clinic if there is a personal or family history (first- or seconddegree relatives) of premenopausal breast cancer, sarcoma, acute leukaemia or
paediatric cancer, especially where two or more of these other cancer types have
occurred and where one or more cases have occurred before age 45.
•
Consider referral of patients with high-grade gliomas to a Cancer Genetics
Service/Familial Cancer Clinic if there is a personal or family history (first- or seconddegree relatives) of bowel, uterine, stomach, ovarian, biliary/pancreatic or small
intestinal cancer or TCC of the upper ureter, especially where two or more cases of these
other cancers have occurred, and/or where one or more of these have been diagnosed
before age 50.
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Northfield DWC. Some Observations on Headache. Brain. 61(2):133–162, 1938.
10
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37
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Forsyth PA, Posner JB. Headaches in patients with brain tumors: a study of 111 patients.
Neurology 43(9):1678–83, 1993.
12
Suwanwela N, Phanthumchinda K, Kaoropthum S. Headache in brain tumor: a cross-sectional
study. Headache 34(7):435–8, Aug 1994.
13
Rushton JG, Rooke E. Brain tumor headache. Headache 2:147–52, 1962.
14
Pfund Z, Szapary L, Jaszberenyi O, Nagy F, Czopf J. Headache in intracranial tumors.
Cephalalgia 1919;discussion.
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Vazquez-Barquero A, Ibanez FJ, Herrera S, Izquierdo JM, Berciano J, Pascual J. Isolated
headache as the presenting clinical manifestation of intracranial tumors: a prospective study.
Cephalalgia 14(4):270–2, 1994.
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Dalessio DJ. Mechanisms of headache. Medical Clinics of North America 62(3):429–42,
1978.
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Frishberg BM. Neuroimaging in presumed primary headache disorders. Seminars in
Neurology 17(4):373–82, 1997.
18
Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical
practice. Acta Psychiatrica Scandinavica, Supplementum 36(149):1–193, 1960.
19
Magnaes B. Body position and cerebrospinal fluid pressure. Part 1: clinical studies on the
effect of rapid postural changes. Journal of Neurosurgery 44(6):687–97, 1976.
20
Matsuda M, Yoneda S, Handa H, Gotoh H. Cerebral hemodynamic changes during plateau
waves in brain-tumor patients. Journal of Neurosurgery 50(4):483–8, 1979.
21
Hayashi M, Kobayashi H, Handa Y, Kawano H, Kabuto M. Brain blood volume and blood
flow in patients with plateau waves. Journal of Neurosurgery 63(4):556–61, 1985.
22
Taphoorn MJ, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol
2004; 3(3):159–168.
23
Tucha O, Smely C, Preier M, Lange KW. Cognitive deficits before treatment among patients
with brain tumors. Neurosurgery 47(2):324–33; discussion 333–4, 2000.
24
Klein M, Taphoorn MJ, Heimans JJ, van der Ploeg HM, Vandertop WP, Smit EF et al.
Neurobehavioral status and health-related quality of life in newly diagnosed high-grade
glioma patients. Journal of Clinical Oncology 2001;(20):4037–4047.
25
Meyers CA, Hess KR. Multifaceted end points in brain tumor clinical trials: cognitive
deterioration precedes MRI progression. Neuro-Oncology 5(2):89–95, 2003.
26
Hom J, Reitan RM. Neuropsychological correlates of rapidly vs. slowly growing intrinsic
cerebral neoplasms. Journal of Clinical Neuropsychology 6(3):309–24, 1984.
27
Kayl AE, Meyers CA. Does brain tumor histology influence cognitive function? NeuroOncology 5(4):255–60, 2003.
28
Freter S, Bergman H, Gold S, Chertkow H, Clarfield AM. Prevalence of potentially reversible
dementias and actual reversibility in a memory clinic cohort. CMAJ Canadian Medical
Association Journal 159(6):657–62, 1998.
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29
Clarfield AM. The reversible dementias: do they reverse?. Annals of Internal Medicine
109(6):476–86, 1988.
30
Smith DF, Hutton JL, Sandemann D, Foy PM, Shaw MD, Williams IR et al. The prognosis of
primary intracerebral tumours presenting with epilepsy: the outcome of medical and surgical
management. Journal of Neurology, Neurosurgery & Psychiatry 54(10):915–20, 1991.
31
Britton JW, Cascino GD, Sharbrough FW, Kelly PJ. Low-grade glial neoplasms and
intractable partial epilepsy: efficacy of surgical treatment. Epilepsia 35(6):1130–5, Dec 1994.
32
Wolf HK, Campos MG, Zentner J, Hufnagel A, Schramm J, Elger CE et al. Surgical
pathology of temporal lobe epilepsy. Experience with 216 cases. Journal of Neuropathology
& Experimental Neurology 52(5):499–506, 1993.
33
Morris HH, Estes ML, Gilmore R, Van Ness PC, Barnett GH, Turnbull J. Chronic intractable
epilepsy as the only symptom of primary brain tumor. Epilepsia 34(6):1038–43, 1993;-Dec.
34
Brainer-Lima PT, Brainer-Lima AM, Azevedo-Filho HR. Ganglioglioma: comparison with
other low-grade brain tumors. Arquivos de Neuro Psiquiatria 2006; 64:613–618.
35
Hirsch JF, Sainte RC, Pierre-Kahn A, Pfister A, Hoppe-Hirsch E. Benign astrocytic and
oligodendrocytic tumors of the cerebral hemispheres in children. Journal of Neurosurgery
70(4):568–72, 1989.
36
Casazza M, Avanzini G, Broggi G, Fornari M, Franzini A. Epilepsy course in cerebral
gangliogliomas: a study of 16 cases. Acta Neurochirurgica–Supplementum 46:17–20, 1989.
37
Hildebrand J, Lecaille C, Perennes J, Delattre JY. Epileptic seizures during follow-up of
patients treated for primary brain tumors. Neurology 65(2):212–5, 2005.
38
Boon PA, Williamson PD, Fried I, Spencer DD, Novelly RA, Spencer SS et al. Intracranial,
intraaxial, space-occupying lesions in patients with intractable partial seizures: an
anatomoclinical, neuropsychological, and surgical correlation. Epilepsia 32(4):467–76, 1991;Aug.
39
Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935
through 1967. Epilepsia 16(1):1–66, 1975.
40
Theodore WH, Katz D, Kufta C, Sato S, Patronas N, Smothers P et al. Pathology of temporal
lobe foci: correlation with CT, MRI, and PET. Neurology 40(5):797–803, 1990.
41
Spencer DD, Spencer SS, Mattson RH, Williamson PD. Intracerebral masses in patients with
intractable partial epilepsy. Neurology 34(4):432–6, 1984.
42
Dam AM, Fuglsang-Frederiksen A, Svarre-Olsen U, Dam M. Late-onset epilepsy: etiologies,
types of seizure, and value of clinical investigation, EEG, and computerized tomography
scan. Epilepsia 26(3):227–31, 1985;-Jun.
43
Lee DH, Gao FQ, Rogers JM, Gulka I, Mackenzie IR, Parrent AG et al. MR in temporal lobe
epilepsy: analysis with pathologic confirmation. Ajnr: American Journal of Neuroradiology
1919;(1):19–27.
44
King MA, Newton MR, Jackson GD, Fitt GJ, Mitchell LA, Silvapulle MJ et al. Epileptology
of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance
imaging study of 300 consecutive patients. Lancet 352(9133):1007–11, 1998.
Clinical presentation
39
45
Pohlmann-Eden B, Schreiner A, Mika A. [Diagnostic and prognostic implications of the first
epileptic seizure in adulthood]. [German]. Fortschritte der Neurologie-Psychiatrie 62(5):147–
54, 1994.
46
Sanson M, Thillet J, Hoang-Xuan K. Molecular changes in gliomas. Current Opinion in
Oncology 16(6):607–13, 2004.
47
Benjamin R, Capparella J, Brown A. Classification of glioblastoma multiforme in adults by
molecular genetics. Cancer Journal 2003; 9:82–90.
48
Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D et al. Phase III trial
of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed
anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J
Clin Oncol 2006; 24(18):2707–2714.
49
Bondy ML, Lustbader ED, Buffler PA, Schull WJ, Hardy RJ, Strong LC. Genetic
epidemiology of childhood brain tumors. Genetic Epidemiology 8(4):253–67, 1991.
50
Riccardi VM. The genetic predisposition to and histogenesis of neurofibromas and
neurofibrosarcoma in neurofibromatosis type 1. Neurosurg Focus 2007; 22(6):E3.
51
Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE et al. The diagnostic
evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis
2. JAMA 278(1):51–7, 1997.
52
Goh S, Butler W, Thiele EA. Subependymal giant cell tumors in tuberous sclerosis complex.
Neurology 63(8):1457–61, 2004.
53
Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P et al. Li-Fraumeni and
related syndromes: correlation between tumor type, family structure, and TP53 genotype.
Cancer Research 63(20):6643–50, 2003.
54
Lindor NM, Petersen GM, Hadley DW, Kinney AY, Miesfeldt S, Lu KH et al.
Recommendations for the care of individuals with an inherited predisposition to Lynch
syndrome: a systematic review. JAMA 296(12):1507–17, 2006.
55
Raffel C. Medulloblastoma: molecular genetics and animal models. Neoplasia 2004;
6(4):310–322.
56
Fountaine T, Lind CR, Law AJ. Primary glioblastomas and anaplastic astrocytoma in a
glioma family. Journal of Clinical Neuroscience 13(4):497–501, 2006.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
5
5.1
IMAGING
Introduction
Neuro-imaging is an integral component of adult glial tumour management and has many roles to
play. This chapter uses the World Health Organization (WHO) tumour grading system for glial
tumours.1 Over the past three decades, there has been a change from invasive techniques which often
demonstrated tumours by indirect means, to advanced cross-sectional imaging modalities which now
directly illustrate these lesions. Computed tomography (CT) and magnetic resonance imaging (MRI)
currently form the mainstay of brain tumour imaging.
Across Australasia there has been a progressive trend to centralise neuroscience resources, mainly
relating to the deployment and localisation of neurosurgical services. All units have access to MRI in
both the public and private sectors. The aims of imaging of brain tumours are primarily to diagnose or
refine a suspected diagnosis and then to optimally localise and characterise them. It is important to
assess for potentially life-threatening changes that may necessitate the use of more emergent
treatment. An imaging diagnosis of a brain tumour may be the result of the assessment of a clinical
syndrome. Screening examinations are only performed in those at high risk of developing a brain
tumour such as neurofibromatosis and other familial or genetic syndromes.
Clinicians require CT and/or MRI imaging in order to plan treatment. This maybe used with
specialised neuronavigation equipment to facilitate stereotactic localisation of the tumour. This
enables the most accurate surgical biopsy or resection and/or radiotherapy treatment for the patient.
This and other specialised MRI sequences can be used to help delineate tumour from vital structures
such as eloquent cortex, arteries and cranial nerves, and assist in planning treatment, such as
positioning the craniotomy and defining the resection margins. Following initial management, CT and
MRI can also be used to quantify therapeutic response, assess the extent of residual tumour and detect
tumour progression or recurrence as well as recognise effects of treatment and complications such as
haemorrhage, contusion and infection. Delayed treatment-induced changes, such as radiation necrosis
and leukoencephalopathies, may also cause deterioration in a patient’s condition, and be difficult to
differentiate from tumour progression on imaging grounds.
This chapter reviews the imaging of glioma from the technology available for lesion diagnosis,
through to surveillance and follow-up. Recommendations are made as to the appropriate imaging
protocols, based on the current literature and teaching hospital standards. There is an inherent problem
with constructing evidence-based guidelines in radiology, in part because of the rapidly evolving
technology in CT, MRI and also nuclear medicine techniques. The levels of evidence as they are
currently described for academic and clinical medicine are not tailored for imaging science and those
currently available cannot and must not be applied to current imaging practice.
Imaging
41
Key points:
•
Neuro-imaging is an essential component of glial series tumour management.
•
CT and MRI form the mainstay of tumour imaging.
•
The main aims of imaging of brain tumours are to:
-
primarily diagnose or refine a suspected diagnosis
-
optimally localise the lesion
-
characterise the lesion
-
assess the lesion’s secondary effects and complications
-
plan surgical and radiation treatment including the provision of input data for
neuronavigation
-
quantify therapeutic response
-
recognise post-treatment progress and complications
5.2
Routine imaging modalities
Historically, plain skull radiography, echoencephalography, early forms of radionuclide brain
scanning, pneumo-encephalography and angiography were amongst the imaging methods used to
indirectly diagnose intracranial space-occupying lesions.2,3 Today, these modalities are no longer
employed in the assessment of brain tumours, apart from angiography when uncommonly, a neurointerventional procedure is contemplated as part of a patient’s management.
5.2.1
Computerised tomography
CT is usually the preliminary investigation when clinical symptoms and signs raise the suspicion of
the presence of an intracranial mass. CT is widely available and is relatively fast and inexpensive
compared with MRI. In addition to confirming the presence of a space occupying lesion and/or
possible brain tumour, CT is helpful in demonstrating the presence of intra-tumoural calcification
which may suggest an oligodendroglial series lesion; as well as assessing those that may have
haemorrhagic components or skull vault or base involvement.
On CT, glial tumours are mostly of low attenuation with variable enhancement patterns depending on
the pathological grading. Atypical lesions may be multifocal and/or have increased attenuation on the
unenhanced studies. On the other hand, lesions of higher-grade may not necessarily enhance. This is
an imaging feature of anaplastic astrocytoma.
The use of iodinated intravenous contrast media in tumour imaging assists in detection and
characterisation. Higher doses of contrast administration are associated with increased lesion
conspicuity.2,4 Demonstrable enhancement in the mass reflects an increase in local tumour vascularity
and contrast leakage from the intravascular compartment due to a disruption of the blood–brain
barrier. In the presence of a glial tumour, contrast enhancement is associated with a higher
pathological grade of tumour.
MRI is contraindicated in patients with ferromagnetic aneurysm clips, cardiac pacemakers, cochlear
implants and intra-orbital metallic foreign bodies. Alternative CT protocols, employing multi-channel
systems and volumetric imaging with multi-planar reconstructions may however suffice for the initial
and subsequent evaluation. CT volumetric studies can also be used as the basis for neuronavigation
42
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
imaging data, when the lesion and/or target is readily visible on CT. A CT angiogram (CTA) may also
be useful if the lesion is in close proximity to intracranial vessels, as an aid to pre-surgical planning.
CT has several limitations; soft tissue resolution of CT images is inferior to that of MRI, in certain
regions of the cranial cavity, such as the middle and posterior cranial fossae, artefacts limit lesion
visibility and therefore interpretation, and iodinated contrast has a risk of hypersensitivity reactions.
5.2.2
Magnetic resonance imaging
All intracranial lesions needing an intervention such as biopsy or resection should have evaluation by
MRI. The technique is superior to CT in many respects as it has excellent soft tissue contrast
resolution, multi-planar capabilities and does not require the use of ionising radiation. Lesions are
more conspicuous and therefore are detected with greater sensitivity than with CT which has a
comparative sensitivity and specificity of 87% and 79% respectively.3 There is, however, no
difference in detection of surgical space-occupying lesions between CT and MRI.5 Differing tissue
components (intra-tumoural heterogeneity) are more likely however to be characterised with MRI, as
is the extent of the tumour. The technique is therefore the preferred modality in subjects in whom
brain neoplasia is a possible diagnosis.
Modern mid magnetic field (1–1.5 tesla) clinical MRI systems produce diagnostic-quality images in a
reasonable time frame. Multi-planar imaging should be performed in all cases to determine the best
surgical approach and to delineate relationships with important structures as well as changes
associated with the mass effect resulting from the lesion.
The use of contrast is imperative to verify components of the tumour and must be used to assist in
grading and local staging. As with CT, enhancement in the tumour matrix reflects an increase in the
local tumour vascularity and a disrupted blood–brain barrier, indicating a higher pathological grade of
tumour. Contrast enhancement will help to identify significant extra information such as meningeal
and ependymal involvement as well as intracranial metastatic disease. Gadolinium-based contrast
media also has a safer risk profile than that of iodinated contrast.
The main aim of the MRI study is to confirm the diagnosis of an intracranial space-occupying lesion
and more importantly, to refine the diagnosis, detect additional findings not seen on the CT, and help
plan more accurately the surgical approach. The majority of lesions are hypo-intense on T1 weighted
imaging, and hyper-intense on T2 studies. Again, there is variable enhancement depending on the
grade. A variety of signals can be seen within lesions resulting from necrosis, proteinaceous material
or haemorrhage.
A basic reproducible MRI protocol is as follows:
a. Fast/turbo spin echo axial T2 weighted study
b. Spin echo sagittal or coronal T1 weighted study
c. Spin echo sagittal, coronal and axial T1 weighted study following the administration of
intravenous gadolinium contrast media
Additional sequences that may help in the lesion evaluation include:
a. Fluid Attenuated Inversion Recovery (FLAIR) studies: A T2 weighted study with CSF
suppression which increases lesional conspicuity6–8 (Class IV evidence)
b. Fat-saturated contrast-enhanced studies are helpful for tumours close to the skull base or
calvarium
Imaging
43
c. Magnetic resonance angiography and venography may assist for lesions closely associated with
the intracranial vasculature
d. Susceptibility weighted/T2 weighted gradient echo studies more readily identify those tumours
with haemorrhagic components
e. Diffusion imaging (see advanced and emerging imaging modalities)
f.
Perfusion imaging (see advanced and emerging imaging modalities)
g. MR spectroscopy (see advanced and emerging imaging modalities)
h. Magnetisation transfer imaging also assists with lesion conspicuity.4,9
i.
Volumetric imaging with multi-planar reconstructions should be performed on MRI to allow
accurate neuronavigation for surgical and radiotherapy interventions (see later). This may include
MP-RAGE (magnetisation prepared rapid gradient echo), SGPR (spoiled gradient echo) or
volumetric T2 or FLAIR acquisitions.
Many of these additional sequences that should or could be added to the basic MRI protocol are of
interest and may provide additional information. However there is no strong evidence that they
improve the cost-effectiveness of outcome in the patient being investigated for a suspected brain
tumour.
MRI technology and scanning comes at a significant increased cost compared with CT and is not as
widely available. In addition to specific medical contraindications to MRI, patients experiencing
claustrophobia may require general anaesthesia or sedation. Furthermore, the evaluation of bony
involvement and calcified or haemorrhagic components is better on CT.
Key points:
•
CT (with or without the use of intravenous contrast) because of its ready availability is
most often the first examination to reveal the possibility of an intracranial neoplasm.
•
CT also helps also with the assessment of calcified and haemorrhagic lesions as well as
those that may involve bone.
•
CT requires the use of x-rays (ionising radiation).
•
Contrast-enhanced MRI is the imaging modality of choice for the diagnostic workup of
an intracranial lesion because of its superior soft tissue resolution and multi-planar
imaging capabilities.
•
MRI has a greater accuracy in lesion depiction compared with CT.
•
MRI is contraindicated in patients with ferromagnetic aneurysm clips, cardiac
pacemakers, cochlear implants and intra-orbital metallic foreign bodies.
5.3
Diagnostic and pre-operative imaging considerations
In patients presenting with neurological syndromes, deciding who should undergo brain imaging to
exclude a neoplasm is difficult and the evidence is limited. Patients with neoplastic brain disease most
commonly present with headaches, seizures and/or focal neurological deficits. However in the
individual patient, the clinical presentation will often depend on the lesion topography.10,11 The
gradual or even relatively acute onset of a clinical syndrome that progresses over time is a helpful
44
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
indicator, with emphasis on the progressive nature of the symptomatology. No combination of clinical
symptoms and signs reliably differentiates brain tumours from other benign aetiologies.12
Imaging can be used to exclude an alternative tumefactive non-neoplastic process, such as infarcts5,13
(subacute, venous), aneurysms, haematomas6,14, cavernous malformations, abscesses7,15,
granulomatous lesions, demyelinating lesions16–22 and other inflammatory pseudo-lesions such as
plasma cell granuloma. Surgical intervention may therefore be either modified or avoided. Nonanatomic physiological imaging methods may also be helpful here. These include MRI diffusion,
perfusion, and spectroscopy.23–25
Age and lesion location are important and may help in predicting tumour type. Despite the
appearances on MRI and CT, for the vast majority of lesions the ability to predict tumour type reliably
remains limited. The final diagnosis is made on histopathology. Presumed radiological diagnosis is
only used to guide non-surgical treatments when surgery is likely to cause significant neurological
deterioration. Examples of these circumstances would be radiotherapy and chemotherapy for
brainstem and optic pathway glioma.8,26
Neuroradiologists and neurosurgeons must use accurate diagnostic techniques that confirm
characteristics of individual glial neoplasms before recommending specific treatments. Ideally, all
patients who are considered to have a presumptive diagnosis of a glial series tumour should be
managed by a multidisciplinary team in a centralised neurosciences centre.
Neuroscience centres must be capable of providing emergency imaging facilities when called for and
able to accommodate patients requiring a general anaesthetic, and the waiting times for brain tumour
patients must be appropriate. For non-urgent cases, a one-week period to complete imaging evaluation
is thought to be acceptable.
Scanning should be supervised by an accredited MRI and/or neuroradiologist. Ideally, all scans
performed outside of the neurosciences centre should be reviewed by the neuroradiological team
before treatment.
Compared with other human tumours, the diffuse cerebral glioma is unique in that the imaging, in
part, reflects histopathological and clinical behaviour.9,27 Low-grade gliomas (LGG) are usually a
focal expansion of neuroparenchyma, with minimal surrounding white matter change and no contrast
enhancement, whereas high-grade gliomas are more space occupying, contrast enhancing and cause
notable surrounding white matter oedema.
Gliomas, particularly high-grade lesions, are also often disseminated at the time of diagnosis, with
tumour cells being detected beyond the margins of the radiographic lesion.28
Histological intra-lesional heterogeneity is a feature of glial series tumours, with extremes of grade,
biological behaviour, gene expression and MR signals sometimes represented in different areas of the
same lesion.29–31 This heterogeneity may be demonstrated or implied by advanced imaging methods,
such as MR spectroscopy and perfusion imaging. Foci of high-grade tumours may be demonstrated in
areas that do not contrast enhance and therefore this feature of the tumour cannot be reliably used for
diagnosis or follow-up. Contrast-enhancing portions may also over- or under-estimate the presence of
active tumour. With this in mind, even if a biopsy specimen is low grade, the presence of contrast
enhancement should alert the clinician to the possibility of a high-grade component to the overall
lesion. This warrants attentive follow-up or further surgical intervention to obtain more diagnostic
material.32
Low-grade glioma (LGG) will grow slowly in size, with a significant proportion undergoing
anaplastic progression to a high-grade glioma (HGG) (also known as secondary GBM).33–36 This may
be seen as increasing T2 change, heterogeneity and contrast enhancement.
Imaging
45
Key points:
•
No combination of clinical symptoms and signs reliably differentiate brain tumours from
benign causes.
•
MRI and CT cannot reliably predict tumour type; biopsy and histological assessment are
required.
•
Standardised tumour imaging protocols are necessary.
•
The timing of imaging must be appropriate to the patient’s clinical state.
•
Scanning should be supervised by an accredited MRI and/or neuroradiologist.
•
Ideally, all scans performed outside of the neurosciences centre should be reviewed by
the neuroradiological team prior to treatment.
•
Gliomas, particularly high-grade lesions, are heterogeneous structurally and are
disseminated at the time of diagnosis.
•
Contrast-enhancing portions may either over- or under-estimate the presence of active
tumour.
•
Low-grade glioma (LGG) will grow slowly in size, with a significant proportion undergoing
anaplastic progression.
5.4
Tumour imaging appearances
The classical appearance of GBM or grade IV tumours is an irregular nodular-ring-enhancing lesion
which has mixed attenuation and signal characteristics on CT and MRI respectively. The lesions are
usually of low attenuation on CT and of high signal on T2 and low signals on T1 weighted MR
imaging. The central non-enhancing component is indicative of cavitation or necrosis. The
enhancement may be of relatively increased attenuation or of low signal on T2 weighted studies,
indicating hypercellularity. There maybe both neoplastic or associated cysts present, and a variable
amount of surrounding �infiltrative’ oedema which is a combination of increased interstitial water,
and neoplastic cells. The tumour tends to infiltrate along white-matter tracts and perivascular spaces,
allowing distant spread with little disruption to the brain.
Low-grade gliomas (LGGs) are poorly defined, low attenuation lesions with minimal mass effect and
surrounding oedema. In a majority of cases there is no contrast enhancement. The lesions are of low
signal on T1 weighted studies and of high signal on T2. Their visibility and definition is better on T2
weighted imaging. While the typical imaging features of a LGG can often be present, LGG cannot be
diagnosed on imaging alone. An exceptional situation arises with lesions such as brain stem and optic
pathway gliomas, where the appearances may be very typical and given the risks of biopsy, adjunctive
treatment is often commenced on the basis of imaging appearances alone.
Oligodendroglial tumours have a similar appearance, but may be located more superficially, are very
commonly calcified and contain areas of cystic degeneration. These lesions show slight or moderate
enhancement with intravenous contrast media.
46
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points:
•
Glial tumours can have imaging characteristics that allow diagnosis and an estimation of
pathological grade, however there is significant overlap and inconsistencies that limit
accuracy of diagnosis. Biopsy is therefore required.
•
The appearances of brain stem and optic pathway gliomas may be very typical and
given the risks of biopsy, treatment is often commenced on the basis of imaging
appearances alone.
5.5
Radiological report
Ideally, the interpretation and reporting of neuro-oncology should be performed by neuroradiologists
and cross-sectional imaging specialists who have a dedicated interest. Reliable and standardised
reporting and review at a centralised unit allows for more comprehensive pre-operative and ongoing
patient management.
A suggested report should include:
1. Identification of factors that may limit the sensitivity and specificity of the examination.
2. Confirmation of presence of a neoplastic lesion.
3. Whether the abnormality is multicentric
4. Imaging characteristics: uniform or variable
i.
T1 and T2 signal characteristics.
ii. Contrast enhancement.
iii. Presence of haemorrhage and necrosis.
iv. Presence of tumour or associated cysts.
v. Infiltrative or vasogenic or cytotoxic oedema.
5. Three-dimensional lesion size, defining what is being measured, for example, contrast-enhancing
portion or T2 change.
6. Anatomical locality.
7. Secondary phenomena:
i.
Mass effect, brain shift and herniation syndromes.
ii. Infiltrative or vasogenic or cytotoxic oedema.
iii. Generalised brain swelling.
iv. Presence of haemorrhage and necrosis.
v. Presence of hydrocephalus.
8. Incidental findings.
9. Comparison with previous examinations (or reports if images not available).
Imaging
47
10. Comments: indicating conclusions of the study, including a differential diagnosis and suggesting
an appropriate follow-up imaging protocol.
If there are features such as brain shift or herniation that may warrant emergency management, it is
recommended that the concerns of the radiologist be directly conveyed to the referring physician so
that early intervention can be considered.
Key points:
•
Reporting of neuro-oncology should ideally be performed by neuroradiologists.
•
The radiological report is a dynamic phenomenon and may change with additional
clinical or ancillary information.
•
More structured and standardised reporting is recommended.
•
If there are features that warrant emergency management, this should be directly
conveyed to the referring physician as soon as possible.
•
It is important to assess and document tumour response to treatment.
5.6
Surgical neuronavigation and intra-operative imaging
Another important function of brain imaging is to optimally localise the tumour prior to surgery. In
addition to routine imaging, �neuronavigation’ has become an important adjunct technique in many
neurosurgical procedures. The central concept of accurately �projecting’ CT or MRI data into the
operative field allows the surgeon to optimise anatomical orientation, better defining anatomical
landmarks, optimally positioning a minimally-sized craniotomy flap, and allowing precise targeting of
pathological structures and tumour margins during operative procedures. Neuronavigation may also
be used for frameless stereotactic biopsy for deep seated lesions where tumour debulking is not
possible.10,37 Pre-operative MRI should include stereotactic data to reduce the need for repeat imaging.
With an average intra-operative �error margin’ of approximately 3–4mm, neuronavigation allows a
more aggressive resection in a greater proportion of cases and hence the achievement of significantly
lower relative residual tumour volumes. This has been shown to be associated with better neurological
and functional patient outcome, with a significant prolongation in survival.38–40 There is improved
surgical safety by minimising adjacent tissue trauma during procedures.11,41–43
Relatively recent technological developments have led to the manufacture of a variety of MRI units
that can be used intra-operatively, providing the surgeon with real-time updated imaging during a
surgical procedure and integrating this with navigation capabilities. The systems have been shown to
improve the extent of resection and increase the proportion of patients in whom complete removal of
the enhancing parts of the tumour can be achieved.44 Studies of intra-operative MRI have revealed
that the surgical objective is not achieved in up to one third of initial unguided resections.17,45
Recent studies have suggested an association between the extent of surgical resection and survival for
neurosurgical patients who underwent surgery for low-grade glioma with intra-operative MRI
assistance. The greater the resection, the longer the survival recorded.46,47–49 Intra-operative MRI is
not yet widely available in Australia. Surgery utilising this technique for patients with grade IV
gliomas has not been convincingly demonstrated to be more efficacious than conventional methods. 50
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points:
•
�Neuronavigation’ projects CT and/or MRI data into the operative field for better
anatomical orientation, better defining of anatomical landmarks, better positioning of
the craniotomy flap, and precise targeting of pathological structures and tumour margins
during operative procedures.
•
Intra-operative MRI can compensate for brain shifts and therefore allows a better
assessment of the extent of resection.
5.7
Post-operative assessment
Most patients with intracranial neoplastic lesions will have some form of operative intervention,
whether it is a biopsy, partial resection, gross total resection, or even a lobectomy. In LGG there is
some evidence that radical surgery does lengthen survival and improve quality of life24,51, however
given the infiltrative nature of glioma lesions, complete resection is rare. CT is routinely used at some
institutions in the early post-operative period to exclude complications such as haematomas and
cerebral swelling that may not be clinically evident. Other institutions only image if there is a clinical
indication. Scans can also be assessed for any gross remaining tumour and it is common practice to
use contrast-enhanced imaging.
Post-surgical enhancement can be seen along the resection margins on approximately the third and
fourth post-operative days. It is usually represented as fine linear, sometime amorphous, nodular
changes and therefore can make the assessment for residual or recurrent tumour challenging. Dural
enhancement is sometimes seen at the craniotomy site. This can last up to six months.52,53
An early post-operative MRI within the first 24 to 48 hours can be used to assess the operative site for
residual tumour. With MRI, treatment-related contrast enhancement can be seen as early as 18 hours
post-operatively, but usually does not appear in the first three to four days. This can been seen for
longer with MRI than with CT, and has occasionally been seen beyond one year following the
surgical intervention.53,54 Scanning in the early post-operative period will also allow assessment with
diffusion imaging (see section 5.8 Follow-up imaging) to assess any contribution of parenchymal
damage to subsequent changes seen in the brain. Haemorrhage is also less likely to interfere with the
visualisation of residual contrast-enhancing tumour on the immediate post-operative study.
MRI is the preferred modality to assess the post-operative status of the brain. As with CT, contrast
enhancement on subsequent imaging can lead to a false interpretation of residual tumour or recurrence
and it may take weeks to resolve a question of treatment-related changes versus tumour if early
scanning is not performed. The method used to assess for residual tumour is based on evaluating for
contrast-enhancing structures. It should be kept in mind that there may be significant components of
tumour, either low or high grade, but which do not exhibit enhancement. Therefore while using
contrast enhancement as the basis of defining residual tumour is imprecise, it is the basis of clinical
practice. Review of the pre-operative imaging may help to identify the imaging characteristics
peculiar to the tumour, which may help in subsequent interpretation. New foci and clumps or nodules
of enhancement associated with extending T2 changes are however more likely to represent tumour.
With evolving post-surgical changes, haemorrhage and parenchymal damage, progressive tumour
may be difficult to exclude in the first three post-operative months. It is important to maintain
standardised imaging protocols that include the utilisation of gadolinium to lessen the difficulties with
interpretation of subsequent or follow-up imaging.
Dural enhancement and thickening in relation to the surgical site is common and even remote dural
changes may present. The question of infection is sometimes raised, however imaging is a poor
discriminator and often the decision is a clinical one. Dural enhancement may persist for years.
Imaging
49
In the early post-operative period, imaging may also be performed for the purposes of guiding
subsequent radiotherapy if indicated.
Key points:
•
Reactive post-operative changes can be seen as early as 18 hours on MRI and can last
for years.
•
Immediate post-operative imaging may help to differentiate between residual tumour,
post-operative reactive changes and parenchymal damage as a result of treatment.
•
Contrast-enhanced MRI is more sensitive in detecting changes compared with CT,
however it still has limitations, notably with high-grade non-enhancing lesions.
•
Adherence to standardised imaging protocols is advised to aid in the interpretation of
subsequent follow-up studies.
5.8
Follow-up imaging
Part of the ongoing care of the oncology patient is imaging to monitor for treatment response and
tumour recurrence or progression, and to assess for any possible treatment-related side effects. No
adequate data exist on the role of imaging in the monitoring of brain cancer response to therapy, even
though this constitutes a substantial part of neuro-oncology imaging.
Given the sensitivity of MRI in demonstrating components of gliomas in pre-operative studies, its use
has now become routine. CT can be used but may be insensitive to early progressive changes if early
intervention is to be considered.
The optimal frequency of these follow-up studies is unknown. Much of common imaging practice is
based on protocols extrapolated from neuro-oncology trials55–59 or empirical clinical practice. Apart
from any immediate post-operative scan, the first baseline examination is usually performed between
six weeks and three months after the completion of definitive treatment, then at 2–3 month intervals.
If the disease is found to be stable, the intervening interval may be increased to 6 months. If however,
there are equivocal findings that may indicate a significant change, an early interval scan should be
prescribed, for example at 4–6 weeks. In the event a patient develops new symptoms, an earlier
examination should be undertaken.
Despite a much more favourable outlook when compared with high-grade glial series tumours,60
routine imaging surveillance of LGG is prescribed to monitor for the signs of malignant
transformation. In the long term this is thought to occur in approximately 50% of lesions and is more
likely in the elderly.61 The volume of T2 hyperintensity is the strongest predictor of overall survival of
patients with supratentorial diffuse astrocytoma (WHO II) and the only predictor of malignant
progression.62 This may be seen as a new focus of progressive T2 signal change or contrast
enhancement. Alternatively, a gradual growth pattern is seen. Oligodendroglioma have been noted to
grow in diameter by about 4mm per year.63 Serial follow-up MRI examinations are performed every
3–6 months as a supposed standard of practice.64
A variety of imaging protocols is employed in follow-up studies, however it is important to maintain
the same protocol to allow accurate comparison. The number of sequences can be minimised by
utilising those that will demonstrate any worrisome changes, such as extension of signal change and
new or progressive contrast enhancement.65 The appearances may be complicated by evolving posttreatment changes.
One of the major limitations is the detection of changes that may indicate a response to treatment and
the ability to differentiate them from those indicating progressive tumour growth. Contrast-enhanced
50
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
MRI usually fails to detect the effects of radiotherapy and chemotherapy at least in the first 12
months.66–68 A reduction in contrast enhancement and T2 changes on MRI may be interpreted as an
imaging improvement and is assumed to be a treatment response, but these findings are non-specific
and may be due to a variety of processes. Comparison should be made with the most recent historical
study; however extending the comparison to scans in the distant past may help to clarify subtle
changes when suspected. This may include surveying the original imaging.
The description of the lesion on follow-up studies should include a measurement of tumour size.
However, quantifying this can be difficult. Lesions are often irregular in outline, heterogeneous in
grading, and have significant necrotic and cystic components. In addition, the contrast-enhancing
portion may not be representative of the tumour as a whole. Orthogonal diameters of the contrastenhancing component/s taken through the lesion on the trans-axial scans have nevertheless been the
process by which objective tumour measurements are made. From this an approximate area or volume
can be calculated. Summary data illustrating the location of measurements will help with interobserver variability when reporting further examinations. Computer-aided volumetric analysis has
been shown to be more reliable and better at detecting early progression. Perimeter measurements
have however been found to be the most sensitive measure of treatment response.69,70
For the purposes of clinical trials, the radiological response is a timelier indicator than survival,
particularly for phase II therapeutic drug trials. This however is reliant on the assumption that an
imaging response is a valid surrogate measure for improved survival. Clinicians must realise that
measuring a change in tumour diameter, area or volume seems potentially an insensitive means of
detecting early treatment response. Classifications for treatment response that are used in phase II and
III clinical trials for malignant glioma include the MacDonald71 and RECIST criteria. See Chapter 3
Clinical trials and research for further discussion.
Given the progressive nature of HGG with a maximum reported two-year survival rate of 26.5%72 ,
complete or partial responses are rare. Progression-free survival (PFS) period, that is, the duration of
stable disease, has been used as alternative method of assessing efficacy in several trials.73,74 However
there is less evidence with GBM that radiographic response is suitable as a surrogate marker for
survival.75 Assessment may be complicated by pseudo-progression seen after treatment.
The changes associated with treatment, usually radiotherapy, can be illustrated on both CT and MRI.
Radiation can cause significant damage to astrocytes and vessels, resulting in a breakdown of the
blood–brain barrier. Acute oedema may be visualised. Radiation-induced demyelination and necrosis
can be seen as early as three weeks to three months.
Delayed radiation damage usually becomes evident between six months and two years, but can occur
many years following treatment. Radiation necrosis is an uncommon irreversible progressive necrotic
mass which is often identical in appearance to that of progressive residual or recurrent HGG and often
mistaken for progressive disease.76 The appearance of radiation necrosis on CT and MRI is that of
irregularly lesions, with nodular, linear, or curvilinear, �soap bubble- ’ or �Swiss cheese-like’ patterns
of enhancement.1,9,77,78 Both radiation necrosis and residual tumour however rarely exist as distinct
entities but more often in combination as a single lesion. However there is often a predominating
process. No adequate data are available on the role of imaging in differentiating between tumour
recurrence and therapy-related changes. Routine anatomic imaging is usually unhelpful; however
metabolic imaging has a suggested theoretical advantage in the differentiation. This includes forms of
SPECT and PET imaging, and MR spectroscopy (MRS). There is, however, insufficient evidence
supporting the routine clinical use of these modalities in this clinical setting (see later sections).
A necrotising leukoencephalopathy is seen in association with chemotherapeutic agents but this is
more common in children than adults. Other entities such as mineralising angiopathy, large-vessel
occlusion, telangiectasia, meningioma and other secondary tumours may occur rarely.
Imaging
51
Key points:
•
The aim of follow-up imaging is to monitor for treatment response, tumour recurrence or
progression and to assess for any possible treatment-related side effects.
•
No adequate data exist on the role of imaging in the monitoring of response to therapy
of gliomas but nevertheless this forms a significant part of neuro-oncology imaging.
•
MRI is the best imaging modality for the follow-up of glial series tumours, however the
optimal frequency of these studies is unknown. Based on neuro-oncology trials, apart
from any immediate post-operative scan the first baseline examination is usually
performed between six weeks and three months after the completion of definitive
treatment, then at two to three month intervals. If the disease is found to be stable, the
interval may be increased to six months.
•
The difficulty in distinguishing between changes that may indicate a response to
treatment and those indicating progressive tumour growth are important limitations of
follow-up imaging.
•
Follow-up neuro-oncology imaging protocols should be standardised.
•
A description of the lesion on follow-up studies should include an objective measurement
of tumour size.
•
Radiation necrosis is an uncommon irreversible progressive necrotic mass which is often
identical in appearance to that of progressive residual or recurrent HGG and exists more
often in combination with residual tumour. No adequate data are available on the role
of imaging in differentiating between tumour recurrence and therapy-related changes.
5.9
Advanced and emerging modalities
Over the past two decades there has been a vast array of research within radiology using advanced
imaging technologies and their application in the neurosciences. This has been particularly evident in
MRI and nuclear medicine. The components of MRI that have been applied to neuro-oncology
include MRS, diffusion imaging, perfusion imaging (which can be performed on CT also), and blood
oxygenation level-dependent functional MRI (BOLDfMRI). These entities no longer specifically
address anatomical pathology but rather pathophysiological changes in disease. A summary of their
applications is provided in Table 5.1 below. These techniques have been implemented in the work-up
of patients with brain tumours, however there is no high-level evidence in the literature indicating
better outcomes or improved cost-effectiveness in the patient being investigated for a suspected brain
tumour.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points:
•
Forms of advanced MRI that have been applied to neuro-oncology include MR
spectroscopy (MRS), diffusion imaging, perfusion imaging and BOLD fMRI.
•
Patho-physiological changes are the focus of these techniques in disease.
•
There is no high-level evidence indicating better outcomes or management costeffectiveness when using these techniques.
Table 5.1
Advanced imaging modalities
Modality
Potential indications
References
MRS
Refinement of pre-operative differential diagnosis
15,79–82
Biopsy site selection
81,83,84
Monitoring treatment response
85
Differentiating tumour from treatment effects
86
Lesion extent
Perfusion imaging
Diffusion imaging
fMRI
5.10
Angioneogenesis (cerebral blood volume)
Tumour grade
Radiation changes versus tumour
87–92
Microvascular permeability
Tumour grade
93–95
Refinement of pre-operative differential diagnosis,
including abscess differentiation.
96–99
Pre-operative information: fibre tractography
Apparent diffusion coefficient (ADC)
Diffusor tensor imaging (DTI)
100–103, 104–
109
Monitoring treatment response:
Apparent diffusion coefficient (ADC)
Diffusor tensor imaging (DTI)
104–109
Monitoring treatment response: convection therapy
106,107
Pre-operative information: eloquent cortex localisation
110–117
Neural reorganisation
118
Nuclear medicine
Historically, nuclear medicine assumed a significant role in the diagnosis of intracranial disease using
99m
Tc DTPA labelled isotopes. This did include tumour detection, but with the advent of direct crosssectional imaging modalities such as CT and MRI, the routine use of nuclear imaging studies in brain
tumour diagnosis has been superseded. There is an extensive body of research initiatives and there are
some specific clinical problems for which scintigraphy may have a role in the management of patients
in some centres.
Imaging
53
Modalities such as single photon emission computed tomography (SPECT) and positron emission
tomography (PET) may help with the understanding of tumour pathophysiology and metabolism.
Both these modalities have improved contrast and spatial resolution compared with two-dimensional
techniques. Significant improvements have also been made in co-registering functional images with
anatomical studies obtained on CT and MRI. This has increased the sensitivity from 65 to 85%.
The tracer most commonly used in SPECT imaging of the brain today is Thallium (201Tl). This has a
limited role in clinical management, but maybe helpful in pre-operative grading of the lesion or in
differentiating between recurrent high-grade glioma and radiation-induced necrosis.119 There is
considerable overlap between grades of tumour120 and other entities such as strokes, scars and
meningiomas.121 The histology of post-radiotherapy brain is usually mixed, with components of
tumour as well as reaction to radiation and surgical injury. The additional clinical information
provided by this form of scintigraphy over that provided by MRI and histology is debatable.122
At a cellular level, PET studies can demonstrate increased cell proliferation. There is a variety of
radioactive tracers, of which18F- fluorodeoxyglucose (18F FDG) is the most commonly used, and
illustrates foci of increased glucose metabolism.123–129 Increased metabolic activity is a feature of
high-grade gliomas, and FDG-PET can help distinguish low-grade from high-grade lesions preoperatively, as well as evaluate the extent of tumour infiltration, find an appropriate site for biopsy130–
133
and demonstrate malignant transformation in low-grade lesions. In the last situation, a new
hypermetabolic focus may appear. The presence of 18F FDG uptake has been shown to be an
independent prognostic risk factor.134–137 The limitations of 18F FDG imaging include the high
background activity of the normal brain and the raised activity exhibited by some low-grade lesions
such as pilocytic astrocytomas, gangliogliomas, and oligodendrogliomas.
PET differentiate recurrent tumour from radiation necrosis with a moderate sensitivity and specificity
of 75% and 81% respectively.138
Another labelled PET isotope used is 11C Methionine. This is associated with less background
parenchymal activity and therefore has increased specificity and sensitivity137,139–143, highlighting foci
of cellular proliferation correlating well with the histological stain Ki-67, and with microvascular
density.144,145 The intensity of uptake correlates with neoplastic grade of the lesion and can therefore
be used to determine a suitable site for biopsy and to define the extent of tumour for radiotherapy
planning.146 Oligodendrogliomas exhibit marked uptake as does ischaemic and inflammatory change,
which limits the specificity of this isotope.131,146–148 This form of PET can be used to assess treatment
response.149
A number of new isotopes traces are being investigated, but their role is yet to be defined.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points:
•
With the availability of CT and MRI, the use of nuclear imaging studies for brain tumours is
no longer routine.
•
The use of scintigraphy is limited to research protocols and some specific clinical
indications in centres with appropriate expertise.
•
Thallium (201Tl) is the most frequently used isotope in neuro-SPECT, and may be helpful in
pre-operative grading of the lesion and differentiating between recurrent high-grade
glioma and radiation-induced necrosis.
•
Fluorodeoxyglucose (18F FDG) is the most commonly used isotope in neuro-PET. This may
have a role in pre-operative grading, evaluating the extent of tumour infiltration, finding
an appropriate site for biopsy, and detecting malignant transformation in low-grade
lesions.
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6
DIAGNOSIS AND PATHOLOGY
6.1
Introduction
Definitive diagnosis of a brain tumour requires histological examination of representative tissue from
the lesion by a qualified and experienced pathologist. Diagnoses based on clinical and or radiological
findings alone should be viewed as presumptive and should not form the basis for definitive treatment
or further clinical management unless there are compelling clinical considerations that preclude
biopsy.
Tissue should be removed from the patient, processed and examined in ways that optimise the
formulation of an accurate diagnosis. The resulting pathology report should include a determination of
the tumour type (astrocytoma or oligodendroglioma) and the tumour grade, and should comment on
any other prognostic or predictive features identified.
The histological diagnosis of brain tumours should be undertaken by a neuro-pathologist or by an
appropriately trained anatomical pathologist with some experience in tumour neuropathology.
6.1.1
Clinical data
Adequate clinical information should be included with the pathological specimen and is essential for
correct diagnosis. This is probably most necessary when an intra-operative consultation (frozen
section) is requested.
As well as demographic data (name, age, and sex), information about the clinical history, the site of
the lesion(s), the radiological appearance, and whether there has been previous treatment (eg surgical,
radiotherapy, chemotherapy) are necessary in order to provide an accurate diagnosis.
6.1.2
Specimen handling
Fresh tissue for intra-operative diagnosis should be obtained without crushing or cautery artefact and
should be transported to the laboratory on a non-absorbent surface (eg Telfa or a non-absorbent plastic
jar). Small specimens should not be placed on gauze or cotton wool as the tissue fragments may
become entangled and difficult, if not impossible, to extract.
6.1.3
Intra-operative consultation
After macroscopic description, small portions of the fresh specimen should be examined by standard
cytological and histological techniques. These may include touch preparations, smears, crush or
squash preparations and frozen sections. Areas of differing appearance should be sampled. Common
pitfalls, often resulting in suboptimal smear preparations, include:
•
trying to smear too much tissue (a 1mm fragment is usually adequate)
•
delaying fixation, resulting in air-drying artefacts.
A number of different stains can be used to examine the cytological preparations, including
haematoxylin and eosin, toluidine blue, peroxidase-antiperoxidase (PAP) and Diff Quik. The
technique(s) adopted will, to some extent, depend on the experience and expertise of the laboratory
and the pathologist.
Part of the specimen should be fixed in formalin for paraffin embedding without freezing since
freezing frequently introduces significant artefacts that may compromise diagnosis. Fresh tissue
should not be placed between surgical sponges prior to fixation as this results in artefactual distortion
of the tissue and may compromise subsequent assessment of cellularity.
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Ideally all tissue removed from the patient should be submitted for pathological examination,
including aspirated material and the material from ultrasonic surgical aspirators. Heterogeneity within
tumours is well documented and in many brain tumour resections, the material routinely submitted for
pathological diagnosis forms only a small part of the actual tissue removed from the patient.
Aspirated tissue fragments, fixed in a large volume of buffered formalin and retrieved by subsequent
filtration, are usually well preserved and allow assessment of intra-tumoural variation. In some cases
this may result in a change in the tumour grade and subsequent management. It is important that this
material remains unfixed in saline for as short a time as possible. The specimen should be received in
the laboratory at the end of the operation and should not remain overnight without fixation.
When material is being collected for tissue banking it is important to ensure that adequate material is
provided for histological diagnosis. A histological diagnosis should take precedence over tissue
banking when the specimen is small.
6.1.4
Pathology report
A pathology report should include at least the following information:
•
demographic and clinical data
•
a macroscopic description of the material received
•
a microscopic description
•
a diagnosis incorporating tumour type (astrocytic, oligodendroglial) and tumour grade
•
identification of any prognostic and/or predictive factors.
A suggested reporting framework is given in Table 6.1. Diagnosis and grading should be based on
standardised and validated criteria. While to some extent these vary over time, currently the World
Health Organization criteria are the most widely accepted.
Diagnosis and pathology
67
Table 6.1
Outline of suggested reporting framework
Demographic and clinical
information
Patient identification and demographic data (age, sex)
Frozen section
Whether part of the sample was frozen and/or used for intraoperative
diagnosis
Clinical information
Whether information was conveyed to the surgeon
Macroscopic description
Number of different specimens received
Specimen labels or other identification
Whether the specimens were received fresh or in formalin
Type of specimen received (fragments, cores or lobectomy)
Specimen dimensions (individual fragments and total)
Appearance and consistency of material
The proportion of the specimen processed paraffin sections including
number of blocks
Microscopic description
A brief histological description of the material documenting the
presence or absence of diagnostic features
Tumour cell lineage (eg astrocyte vs oligodendrocyte)
Tumour grade
Cellularity
Cytological atypia
Mitotic figures
Necrosis
Vascular proliferation
Infiltration into other tissues
Treatment effects
Diagnosis
Diagnostic classification based on World Health Organization criteria
Numerical grade and grading system (eg WHO grade II)
Comment
6.1.5
This may include information about the representativeness of the
specimen (eg a single stereotactic biopsy core from a large mass), the
presence of prognostic or predictive features, or suggested further
investigations (eg genetic analysis or referral for a second opinion).
Grading
Although there is a gross correlation between proliferation, as measured by the MIB-1/Ki-67
proliferation index, and clinical outcome, there is some overlap in proliferation index between diffuse
and anaplastic astrocytoma, anaplastic astrocytoma and glioblastoma, and oligodendroglioma and
anaplastic oligodendroglioma. Consequently, in an individual case, the Ki-67 labelling index cannot
be used to assign tumour grade. However, since grade II and grade III astrocytomas are distinguished
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by the presence of mitotic activity in the latter, it has been suggested that MIB-1 labelling indices may
more reliably separate grade II from grade III tumours in some situations, especially when only a
small specimen is available for analysis.1
6.1.6
Prognostic and predictive features
Tumour grade is the single most important prognostic feature (see Chapter 1 Epidemiology).
Currently there is no validated factor that unambiguously predicts tumour progression from diffuse
astrocytoma (WHO grade II) to anaplastic astrocytoma (WHO grade III) and glioblastoma multiforme
(WHO grade IV) in individual patients.
6.1.7
Tumour heterogeneity, sampling and inter-observer variation
As in other tumours, morphological and genetic heterogeneity is well documented in gliomas. Only
part of this heterogeneity is identified radiologically. Consequently it should be remembered that the
material examined and reported on may not be representative of the entire lesion. Correlation with the
radiological and other findings is important, especially when the specimen examined is small. For
example, a pathological diagnosis of �fibrillary astrocytoma WHO grade II’ for a tumour with
significant contrast enhancement suggests a sampling problem.
There is considerable inter-observer variation in the diagnosis and grading of gliomas. This is most
marked for the diagnosis of tumours with an oligodendroglial component, including
oligodendroglioma (grade II), anaplastic oligodendroglioma (grade III), oligoastrocytoma (grade II)
and anaplastic oligoastrocytoma (grade III). This in part stems from the lack of a reliable reproducible
marker for oligodendrogliomas. Panel review of anaplastic oligodendrogliomas and anaplastic
oligoastrocytomas from the EORTC Trial 26951 demonstrated large discrepancies between the
diagnoses provided by the submitting local pathologists and those provided by an independent panel
of nine neuro-pathologists. For anaplastic oligodendrogliomas, a consensus diagnosis was reached in
52% of the cases that were submitted with a diagnosis of anaplastic oligodendrogliomas, and in only
8% of cases that were submitted with a diagnosis of anaplastic oligoastrocytoma. There was also
considerable inter-observer variation within the panel of experts.2
Review by an expert neuro-pathologist is recommended to reduce diagnostic error.
6.1.8
Genetic testing
Although extensive and ongoing genetic research has increased our understanding of the biology of
brain tumours, at present the use of genetic analysis as part of the standard diagnosis and management
of brain tumours is more restricted and is somewhat controversial. Due to the rapid and continuing
developments in this area, current guidelines are likely to be rapidly superseded.
Currently, genetic analysis does not provide diagnostic information but, in certain circumstances, it
provides prognostic and predictive information.
6.1.9
1p/19q loss
Although concurrent loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19
(19q) is identified in up to 80% of oligodendrogliomas, this is not a diagnostic criterion for this
tumour. The absence of these abnormalities does not exclude the diagnosis of oligodendroglioma.
In anaplastic oligodendrogliomas, the presence of 1p/19q loss is an independent prognostic factor
associated with increased survival.3 1p/19q status also predicts increased likelihood of a response to
therapy, radiotherapy and/or chemotherapy (with procarbazine, CCNU and vincristine [PCV] or
temozolomide). Although in WHO grade II oligodendrogliomas, 1p loss with or without 19q loss is
associated with prolonged survival, it is unclear whether 1p/19q status predicts treatment response.4
1p/19q loss of heterozygosity (LOH) may also be predictive of prognosis for astrocytomas.5,6
Diagnosis and pathology
69
Since it provides prognostic information, genetic testing for loss of 1p/19q is recommended for all
tumours with an oligodendroglial component.
The commonly used techniques for identifying 1p and 19 q allelic loss, namely fluorescence in situ
hybridisation (FISH) or loss of heterozygosity (LOH) analysis, appear to have similar sensitivities and
specificities. A disadvantage of LOH analysis is that is requires a specimen of the patient’s nontumour DNA, usually from a blood sample. This complicates retrospective analyses or the use of
archived material.
6.1.10
Testing of glioblastomas for MGMT promoter methylation
MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that reverses damage
brought about by environmental as well as therapeutically administered alkylating agents. Expression
of MGMT protein in tumour cells renders them relatively resistant to alkylating chemotherapeutic
agents.
Normal cells almost invariably express MGMT protein, whereas many cancer cells do not. It is
thought that the absence of MGMT in cancer cells gives them a selective advantage because
unrepaired DNA mutations generate cancer cell variants which may have a selective in vivo growth
advantage. The selectivity of alkylating agents for tumours is in part related to the differential
expression of MGMT protein in normal versus tumour cells.
Expression of MGMT is controlled by the upstream gene promoter. In many cancers examined, lack
of MGMT and mRNA expression is related to hypermethylation of cytosine residues (CpG islands) in
the promoter region blocking gene transcription, although other mechanisms, including posttranscriptional silencing, have been reported.
Clinical relevance
Silencing of MGMT protein expression, chiefly through promoter methylation, is a recently
recognised phenomenon in glioblastomas and is associated with a good response to alkylating
chemotherapy, particularly temozolomide (Temodarв„ў, Temodalв„ў), and markedly improved patient
survival as compared to glioblastomas expressing MGMT with an unmethylated MGMT gene
promoter.7,8 MGMT promoter hypermethylation occurs in up to 75% of glioblastomas.
The ability of cancer cells to express MGMT is assessed by tests for MGMT promoter
hypermethylation, for example, methylation specific PCR (MSP) or methylation-sensitive highresolution melting of PCR amplimers (MS-HRM), either alone or in combination with
immunostaining for MGMT protein.
In Australia, at present, the decision to give temozolomide to patients with glioblastoma is rarely
influenced by knowing the MGMT status of the tumour, as MGMT testing is seldom performed,
despite the fact that some clinical data support such testing.7,9 MGMT testing may not become routine
in the management of patients with glioblastoma until the biological mechanisms whereby promoter
methylation affects tumour behaviour are clarified and the results of larger clinical trials are known.
Although it is common practice to treat all patients with glioblastomas with temozolomide, as the
drug has an excellent therapeutic effect, in some patients knowing that the MGMT promoter is not
methylated in tumour cells may influence the decision to discontinue treatment if there is little or no
response.10 Discrepancies in the laboratory testing of MGMT also need to be assessed and rectified.
6.1.11
Tumour tissue banking
If available and following informed consent from the patient, consideration should be given to
depositing part of the specimen not required for diagnosis in a tumour bank. Serum should be
collected at the same time as the tissue is collected to optimise translational research opportunities.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Tumour banks also require a clinical dataset to accompany each specimen. This will facilitate brain
tumour research and will provide an important resource that facilitates better understanding of the
biology of brain tumours for improved diagnosis and treatment in the future. Brain tumour banks are
operating in most Australian capital cities.11
Key point:
•
The histological diagnosis of brain tumours should be undertaken by a neuro-pathologist
or by an appropriately trained anatomical pathologist with some experience in tumour
neuropathology.
•
Ideally all tissue removed from the patient should be submitted for pathological
examination, including aspirated material and the material from ultrasonic surgical
aspirators.
•
A pathology report should include at least the following information: demographic and
clinical data; a macroscopic description of the material received; a microscopic
description; a diagnosis incorporating tumour type (astrocytic, oligodendroglial) and
tumour grade; and identification of any prognostic and/or predictive factors.
•
A histological diagnosis should take precedence over tissue banking when the specimen
is small.
References
1
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al. The 2007 WHO
classification of tumours of the central nervous system. Acta Neuropathol 2007; 114(2):97–
109.
2
Kros JM, Gorlia T, Kouwenhoven MC, Zheng PP, Collins VP, Figarella-Branger D et al.
Panel review of anaplastic oligodendroglioma from European Organization For Research and
Treatment of Cancer Trial 26951: assessment of consensus in diagnosis, influence of 1p/19q
loss, and correlations with outcome. J Neuropathol Exp Neurol 2007; 66(6):545–551.
3
Aldape K, Burger PC, Perry A. Clinicopathologic aspects of 1p/19q loss and the diagnosis of
oligodendroglioma. Arch Pathol Lab Med 2007; 131(2):242–251.
4
Giannini C, Burger PC, Berkey BA, Cairncross JG, Jenkins RB, Mehta M et al. Anaplastic
Oligodendroglial Tumors: Refining the Correlation among Histopathology, 1p 19q Deletion
and Clinical Outcome in Intergroup Radiation Therapy Oncology Group Trial 9402. Brain
Pathol 2008.
5
Pinto LW, Mahler Araujo MB, Vettore AL, Wernersbach L, Leite AC, Chimelli LM et al.
Glioblastomas: correlation between oligodendroglial components, genetic abnormalities, and
prognosis. Virchows Arch 2008.
6
Iwamoto FM, Nicolardi L, Demopoulos A, Barbashina V, Salazar P, Rosenblum M et al.
Clinical relevance of 1p and 19q deletion for patients with WHO grade 2 and 3 gliomas. J
Neurooncol 2008.
7
Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V et al.
Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to
alkylating agents. N Engl J Med 2000; 343(19):1350–1354.
Diagnosis and pathology
71
8
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al. MGMT gene
silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10):997–
1003.
9
Chinot OL, Barrie M, Fuentes S, Eudes N, Lancelot S, Metellus P et al. Correlation between
O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed
glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 2007;
25(12):1470–1475.
10
Yip S, Iafrate AJ, Louis DN. Molecular diagnostic testing in malignant gliomas: a practical
update on predictive markers. J Neuropathol Exp Neurol 2008; 67(1):1–15.
11
Barnett GH. Translational research in gliomas: Quo Vadis? Clin Neurosurg 2006; 53:154–
156.
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7
7.1
LOW-GRADE ASTROCYTOMAS
Introduction
This chapter will deal with the management of low-grade astrocytomas (LGA) only. It specifically
will not include the management of low-grade oligodendrogliomas, juvenile pilocytic astrocytomas,
pleomorphic xantho-astrocytomas, gangliogliomas and other non-astrocytomatous or mixed glial
tumours. It will include a discussion of both adult and paediatric low-grade astrocytomas under
separate headings. The authors recognise the controversial nature of this topic and identify several key
areas where there is not consensus. The classification of low-grade astrocytomas, the diagnosis, the
imaging characteristics, the treatment and follow-up all present interesting polarising schools of
thought.
The epidemiology of LGAs is given in Chapter 1 Epidemiology.
7.2
Diagnosis
7.2.1
Clinical presentation
Common presenting symptoms of LGAs include epilepsy, headache, mental changes and focal
neurological deficit. Epilepsy is the presenting symptom in more than half of all cases.1,2 Headache
and focal neurological deficit occur less frequently, and signs of raised intracranial pressure with
papilloedema are uncommon.1
7.2.2
Conventional imaging
Magnetic resonance imaging (MRI) is the imaging modality of choice. MRI is the most sensitive test
available to diagnose LGAs. CT scanning is often the initial study performed and in a typical case
reveals a non-enhancing low-density lesion. Mass effect upon the surrounding ventricular structures is
common. If enhancement does occur, it is generally faint and homogeneous. On the MR images, the
lesion typically presents as a low-intensity area on T1-weighted images whereas there is almost
always an increased relaxation time on T2-weighted images. The area of increased signal is usually
homogeneous and well circumscribed, with no evidence of haemorrhage or necrosis.3 Enhancement
on CT or MRI occur in between 8 and 15% of cases.4-6
Despite the general acceptance of standard MRI as the primary diagnostic tool in assessment of
LGAs, the classification of gliomas with conventional MRI can be unreliable, with the sensitivity
ranging from 55% to 83%7-11 For instance, Knoop et al11 showed that almost one fifth of
glioblastomas do not show enhancement.
Similarly, tumour cells can extend beyond routine CT and MRI-defined boundaries.12,13 Tumour
margins may be better defined with the use of diffusion tensor imaging14 (see Chapter 5 Imaging).
7.2.3
Advanced MRI techniques
Advanced MRI techniques such as perfusion MR and proton MR spectroscopy (MRS) have found
increasing utility in evaluation of glial tumours. Theoretically, the advantage of MRI techniques in
evaluating cerebral gliomas is the ability to sample the entire lesion as well as surrounding brain.15
It has been suggested that dynamic contrast-enhanced T2-weighted MRI may identify more malignant
areas within an astrocytoma.11 Relative blood volume (rCBV) measurements from dynamic
susceptibility contrast perfusion MRI have been shown to correlate with microvascular density in
gliomas16, which are independent prognostic markers for low-grade astrocytomas.17 rCBV maps and
measurements have been shown to correlate with tumour grade.11,18-28
Low-grade astrocytomas
73
Magnetic resonance spectroscopy may have a role in the diagnosis of LGA. Specifically, elevation in
choline with depression of N-acetylaspartate (NAA) is a reliable indicator of tumour. Also, there is a
considerable literature that shows the metabolite ratios of choline/creatinine, and myoinositol/creatinine, and the presence of lipids and lactate may be useful in grading tumours and
predicting malignancy.29
The role of magnetic resonance spectroscopy (MRS) in the diagnosis of low-grade astrocytoma has
been controversial. A recent systematic review has evaluated the role of MRS in the characterisation
of brain tumours.29 In relation to LGAs, MRS may aid in differentiating high- from low-grade
astrocytoma. Five studies have addressed this issue and four of these showed that MRS was highly
sensitive and specific in this regard.30-34 However the data on the ability of MRS together with regular
MRI to accurately predict the nature and grade of glial tumours is questionable. In addition, there are
few studies that use this technology to differentiate LGAs from other lesions that can resemble LGAs
on regular imaging.
Law et al35 have assessed the role of rCBV and MRS in the evaluation of cerebral gliomas. Both
techniques offer much when attempting to differentiate low- from high-grade gliomas, since when
compared to a sensitivity of conventional MRI of 72%, rCBV was 95% sensitive and MRS was
approximately 97% sensitive using choline/creatinine and choline/NAA ratios. These authors36 have
suggested that perfusion MRI and MRS may overcome the limitation of sampling error that exists
with histological analysis by their ability to sample the entire lesion non-invasively.
Law et al37 have provided evidence that rCBV provides a better predictor of behaviour of low-grade
gliomas (including astrocytomas, oligodendrogliomas and oligoastrocytomas) than histological
analysis. These authors point out that histopathological assessment has significant limitations for the
following reasons:
•
only small samples of tissue are assessed, particularly from stereotactic biopsy, and the most
malignant part of the tumour may not be sampled (sampling error)
•
obtaining a specimen may be difficult from eloquent brain (any part of the brain that has a defined
function, the loss of which will lead to major functional impairment)
•
classification systems are inconsistent
•
there is significant intra- and inter-pathologist variation in diagnosis
•
glial tumours are dynamic and tend to dedifferentiate to higher grades over time. In this study of
35 patients, including 21 with LGAs, rCBV showed a significant negative association with
disease-free survival, that is, low rCBV values were associated with longer times to progression.
Lesions with rCBV <1.75 had a median time to progression of 4620 +/ 433 days compared to
lesions with rCBV >1.75, where the median time to progression was 245 +/ 62 days.
Based on their study, Law et al37 have proposed that rCBV be used as an important factor when
deciding on appropriate treatment of LGGs. Primarily, rCBV can be used to decide whether patients
should undergo adjuvant radio- and/or chemotherapy after maximal surgery (if rCBV >1.75), rather
than observation with serial imaging with a low risk of progression (rCBV <1.75). In addition the
authors suggest that with a high rCBV, a more aggressive approach to surgical management could be
undertaken in the knowledge that these tumours are likely to progress rapidly.
rCBV and MRS may also have a role in predicting the grade of oligodendroglial tumours.38
7.2.4
ADC maps
A recent study has shown that apparent diffusion coefficient (ADC) maps, derived from diffusion
weighted images, can show differences between low-grade astrocytomas and oligodendrogliomas.39
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
7.2.5
Positron Emission Tomography (PET)
There may be a role for positron emission tomography (PET) in the diagnosis and treatment of
patients with LGA. LGAs are typically hypometabolic and therefore �cold’ on PET scanning. Highgrade areas tend to be hypermetabolic and therefore will appear as a �hot spot’ on PET scanning. This
information may be valuable in determining the aggressiveness of therapy.40,41 Different PET
methodologies have been used to differentiate low- from high-grade gliomas, including 13N-ammonia
PET42 and methionine43 with the former showing some ability to differentiate astrocytic from nonastrocytic low-grade gliomas.42
Key point:
•
Definitive diagnosis cannot be made on imaging alone. The presence or absence of
enhancement offers some guidance but is not absolutely specific. Non-enhancing
tumours may be high grade. Enhancing tumours may be low grade.
7.3
Management of LGAs
Management of the patient with a LGA starts with compassionate and well-informed delivery of
information. It is incumbent on the physician to ensure the patient and family members are informed
of treatment options and the controversial nature of these recommendations. Naturally, the doctor may
introduce his/her own bias as this is almost impossible to avoid. Responsible informed consent does
not preclude personal bias as long as options are given.
Often these cases are reviewed in multidisciplinary brain tumour conferences.
Key points:
•
If the patient has been informed of all the pros and cons of a conservative approach
and elects to wait then this is reasonable. This option is especially applicable if the tumour
is less than 10cm3 in volume, diffuse on T2 MRI scan and in an eloquent area.
•
Once progression has been documented treatment should be offered before the onset
of fixed neurological deficits.
Without definitive evidence of the benefit of surgery, an accepted recommendation has been a
complete avoidance of surgical intervention. Given that the reliability of biopsy is variable and that
current imaging techniques may confer better prognostic information (see below) this would appear to
be an acceptable option. Patients with diffuse LGA in eloquent areas face some risk of deterioration
following a needle biopsy but it is possible to biopsy many low-grade astrocytomas with acceptable
risk. The resectability of a low-grade astrocytoma depends very much on its extent and the part of the
brain that is affected. The more eloquent brain involved the more difficult it is to obtain a resection
without causing significant morbidity. Some patients may understandably find this risk unacceptable.
This raises the obvious question of what radiological or clinical changes should provoke a more
aggressive approach.
If waiting for tumour growth, what rate of growth is unacceptable and why should delayed surgery be
any safer than upfront surgery? If waiting for contrast enhancement, is this not akin to closing the gate
after the horse has bolted? If waiting for clinical deterioration, would this not negatively influence
quality of life and ultimately the patient’s functionality? Therefore, this conservative approach needs
to be balanced with the negative effects of waiting. There is some evidence that waiting for tumour
progression such as the onset of neurological deficits, growth of tumour and contrast enhancement
may negatively affect the time to progression (TTP) and overall survival (OS). The other argument
against waiting is that upfront surgery may subject the patient to the potential for neurological deficit
Low-grade astrocytomas
75
but at least there is a real chance of neurological status quo, whereas waiting for a deficit to develop
precludes any chance of being neurologically normal.
7.3.1
Establishing a histological diagnosis
Histopathological analysis is generally considered the gold standard in determining diagnosis and
tumour grade. Biopsy, although safe, is not as accurate as open resection in providing specimen for
histological analysis. A recent study demonstrated that patients who underwent biopsies, and
subsequent resection, had an accurate diagnosis in 76% of cases, and in 91%, biopsy predicted the
appropriate therapy.44 Framed and frameless techniques were equivalent. Although the authors stated
that biopsy was accurate in predicting therapy, their own results imply that in almost one in ten
patients who underwent biopsy, their therapy would have been different had more specimen been
available for analysis.44
Stereotactic biopsy has limitations due to sampling error. Jackson et al45 showed that in almost half of
glioma cases, there was a discrepancy in diagnosis between initial biopsy diagnosis and diagnosis
after subsequent resection. Therefore when deciding on management options, reliance on limited
biopsy information may be misplaced.
Key points:
•
Histological diagnosis may be unreliable because of sampling error.
•
Pre-operative MR imaging may have a closer correlation with survival than histological
grading on biopsy.
7.3.2
Attempt at complete macroscopic resection
All primary glial tumours have indiscrete borders. There is never a capsule and even when there
appears to be a well-defined tumour/brain interface, histological studies would suggest otherwise.
Terminology in the literature is extremely variable. Authors may be referring to the same situation
when they talk about complete removal, near-complete removal, complete macroscopic removal and
radical sub-total resection. For the sake of uniformity, we use the term complete to describe a
resection that results in a post-operative MRI that shows absolutely no residual enhancing or nonenhancing tumour, acknowledging that there are residual tumour cells within the surrounding
�normal’ brain; the term near complete to describe a >95% resection by volume: and the term subtotal to describe a <95% resection.28
The first and clear advantage of tumour resection is reduction in the incidence of sampling error.
There is also the opportunity of sending tumour for cytogenetic evaluation and tumour banking, both
of which have therapeutic implications.
The second and less clear advantage of tumour removal is the ability to achieve a curative resection.
Unfortunately, attempts at complete resection, although advocated by many, have been achieved by
few, so definitive statements cannot be made. However, complete macroscopic resection may confer a
survival benefit. This benefit negatively correlates with the amount of residual tumour; the more
residual, the shorter the TTP and OS. There may also be a lower rate of malignant transformation with
reduced tumour bulk.46
Other indications for surgical resection are for intracranial hypertension, restoration of CSF pathways,
improvement of epilepsy and in a few patients, palliation of symptoms.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
7.3.3
Technique of surgery for LGA
Standard microsurgical techniques are used for removal of LGAs. The introduction of frameless
stereotactic technology, endoscopy, tumour labelling and intra-operative MR imaging, has increased
surgeons’ confidence, but these tools have yet to make a statistical impact on survival. Awake
craniotomy and intra-operative cortical mapping may reduce the risk of permanent post-operative
neurological damage but offer no survival advantage. Indeed, the incidence of complete resection is
reduced with both these techniques and they may, in fact, negatively affect survival.
7.3.4
Defining degree of resection
Clinical estimate of resection is invariably incorrect. The best method of determining the degree of
resection (DOR) is to perform a post-operative MRI scan within 48 hours of surgery. This should be
done with contrast medium and any nodular enhancement should be interpreted as residual disease.
Linear enhancement around the tumour cavity may be post-operative changes. Of course, if another
sequence showed the tumour better pre-operatively then this sequence should be used to determine
DOR.
Key points:
•
There is definitely a role for attempted resection of a LGA. It should probably be done at
the time of diagnosis for the following potential benefits: more accurate diagnosis,
palliation of symptoms, extension of survival, reduced chance of malignant
transformation and possible cure.
•
Recommendation of resection should be tempered if the tumour is diffuse, located in an
eloquent area or less than 10cm3 in volume.
•
Standard microsurgical techniques should be employed with the addition of stereotactic
guidance if available.
•
Awake surgery or cortical mapping are optional but may reduce the incidence of postoperative neurological deficit if the aim of surgery is to palliate and secure a diagnosis
rather than prolong life or achieve a cure.
7.3.5
Unique sub-types of LGAs
Brainstem LGA
Brainstem LGAs can be found in children and adults. Most brainstem gliomas are malignant and the
juvenile pilocytic sub-type (JPA) is seen in the paediatric population. JPAs usually enhance relatively
uniformly, whereas the malignant glioma exhibits patchy enhancement. The treatment algorithm is
similar to other brainstem tumours. If the tumour is focal, attempt at surgical resection may be
considered. This has resulted in improved long-term survival and a significant incidence of cure.47 If
the tumour diffusely enlarges the pons, despite having low-grade features, no surgical intervention is
recommended.
Tectal LGA
LGAs located in the tectum of the midbrain behave uniquely. They are typically extremely slow
growing or remain quiescent for entire lifetimes. Indeed, their biological inertia has led some to label
these lesions as hamartomas. They present with hydrocephalus from secondary aqueduct stenosis
necessitating treatment of the hydrocephalus only. The recommended treatment is endoscopic third
ventriculostomy. Shunting may be required if this operation fails. Biopsy or resection of the tumour is
indicated when there is discernible growth or new contrast enhancement. There is an association with
Neurofibromatosis Type 1 (NF1).
Low-grade astrocytomas
77
Optic pathway/hypothalamic LGA
These have also been associated with NF1 but can occur sporadically. They are more commonly seen
in children and can present early (<3 yrs of age) or late. Most tumours in this area are LGAs but there
is a more aggressive variety, the pilomyxoid type, which occurs in younger children, presents with
hypothalamic dysfunction and has a higher incidence of recurrence. Surgical intervention is reserved
for those patients in whom there is CSF obstruction, and clinical or radiological progression despite
all other attempts to inhibit the tumour’s growth. The aim of surgery, given the high-risk location, is
to achieve a radical but sub-total resection.
7.4
Adjuvant therapy of low-grade astrocytoma
Once biopsy or resection has allowed histological confirmation of the diagnosis of low-grade
astrocytoma (LGA), the question of adjuvant treatment must be addressed. Many LGA patients will
be well and asymptomatic post-surgery, and any additional treatment thus requires careful
consideration of its benefits, such as improving overall survival, in comparison to potential toxicity.
7.4.1
Radiotherapy
Based on current available evidence, radiotherapy remains the gold-standard adjuvant therapy. The
major issues in relation to radiotherapy are optimal timing, optimal dose, volume to be treated, benefit
of additional chemotherapy, and toxicity, particularly the contribution of radiotherapy to the longterm neurocognitive problems experienced by many patients with LGG.
LGA is undoubtedly a radio-responsive disease. Although response assessment using conventional
criteria (radiological/clinical evidence of complete response, partial response, stable disease,
progressive disease) is not common in radiotherapy studies, there are other data supporting the
sensitivity of LGA to radiation. Retrospective studies showing an apparent survival advantage for
radiotherapy48-50 cannot be regarded as definitive confirmation, with selection bias a concern.
However, compelling evidence has been provided by the EORTC study 2284551 in which 311 adults
were prospectively randomised to initial post-operative observation or to radiotherapy. Patients in the
radiotherapy arm had a significant benefit in progression-free survival (PFS), with median PFS of 5.3
years in the early radiotherapy group versus 3.4 years in the initial observation group (hazard ratio
0.59, p<0.0001), and five-year PFS of 44% and 37% (p=0.02), respectively. Seizure control at one
year was also noted to be superior in the radiotherapy arm (41% versus 27%). Despite this evidence of
response to radiotherapy and improved progression-free survival, the study did not demonstrate a
significant survival advantage for early radiotherapy, with median overall survival (OS) in the
radiotherapy group 7.4 years compared with 7.2 years in the initial observation group (hazard ratio
0.97, p=0.872). Sixty-five percent of patients in the initial observation group had radiotherapy at the
time of progression, and the equivalent overall survival in this group suggests that LGA is equally
responsive to radiation in the delayed setting. Based on these results, consensus opinion is that for the
majority of LGA patients, an initial policy of observation post-surgery is appropriate, with treatment
being deferred until there is clear radiological or symptomatic progression. The policy of initial
observation is not appropriate for patients with high-risk features (EORTC prognostic score 3–5, see
Table 7.1), who demonstrate early progression and poor median survival. These patients should
proceed to early radiotherapy. LGA in the brainstem represents another special category. Because of
its rarity, the published literature is small, but most patients are symptomatic at presentation and
unsuitable for resection, thus early radiotherapy is appropriate.
The question of radiotherapy dose has been addressed in the EORTC study 2284452, and the
Intergroup study conducted by the North Central Cancer Treatment Group (NCCTG), the Radiation
Therapy Oncology Group (RTOG) and the Eastern Cooperative Group (ECOG).53 These studies
randomised 211 and 379 adults respectively to low- ( 50Gy) versus high-dose RT (59.6 or 65Gy).
There was no difference in the five-year OS or PFS rates between the two dose groups in either study,
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
and the rate of complications such as radiation necrosis was higher in the high-dose group. Current
consensus is that a dose of 45–50Gy represents the optimal balance between efficacy and toxicity.
The volume of brain irradiated in LGA patients has progressively decreased over the past two
decades. Early stereotactic biopsy studies demonstrated that tumour cells frequently extended beyond
imaging abnormalities, and the subsequent use of large margins to define radiotherapy target volumes
resulted in essentially whole-brain radiotherapy for many patients. However, later prognostic factor
analysis showed no improvement in outcome for larger volumes54,55, and indeed there was evidence
that larger volumes were associated with an increased risk of neurocognitive disability.56-58 Analysis
of patterns of failure in the EORTC Study 22845,52 in which margins were 1–2cm beyond the imaging
abnormalities, demonstrated that over 90% of recurrences were within the irradiated volume. Thus
there appears to be no rationale for chasing microscopic disease beyond the obvious imaging
abnormalities, and a conformal approach, using margins of 1–1.5cm only beyond the T2-defined MRI
abnormality, is recommended. The use of stereotactic radiotherapy or interstitial brachytherapy does
not appear to improve LGA outcomes beyond those of standard conformal techniques.59
The potential for debilitating radiation-related late toxicity, particularly neurocognitive deficits, is of
great concern in a population where prolonged survival is common. Although surgery60,
chemotherapy60 and use of anti-epileptic drugs58 have all been demonstrated to result in complications
including impaired neurologic function, the development of neurocognitive deficits in LGA patients
has usually been attributed to radiotherapy. Radiotherapy to the brain has certainly been shown to be
associated with radiological evidence of white matter changes, specific cognitive deficits, and
radiation necrosis. The risk of radiation necrosis is very low but is not clearly established and appears
dose-dependent53 and it is rarely fatal. There is no evidence that radiotherapy results in an increased
risk of high-grade transformation of LGA.52
It is uncertain whether radiotherapy causing significant neurocognitive disability in LGA patients is
problematic.61 The limited evidence of neurocognitive side effects is almost exclusively retrospective,
and includes studies in which many patients were treated with techniques that are no longer standard.
There are intrinsic biases in some studies, and the interaction between total dose, dose fraction,
treatment volume, use of chemotherapy, tumour recurrence, pre-existing neurologic morbidity, and
the development of neurocognitive deficits, is not well studied. Crossen’s review57 of patients treated
with therapeutic brain radiation in 29 studies found that 28% had some degree of late encephalopathy
attributed to radiation, with severity related to patient age, total dose of irradiation, fraction sizes, and
timing of chemotherapy. Klein’s multi-centre study of 195 patients with low-grade glioma58 also
found the use of radiotherapy to be associated with poorer cognitive function; however, cognitive
disability in the memory domain was found only in radiotherapy patients who received fraction doses
exceeding 2Gy. This study also compared quality of life and cognition in low-grade glioma patients
treated with either early or delayed radiotherapy, with those of a control group suffering from
haematological malignancies. Both low-grade glioma groups had significantly worse cognitive
function than the control group. It may be that the tumour itself, and particularly tumour progression,
is the major determinant of cognitive function, rather than radiotherapy.62 This is supported by an
extensive literature review by Brown et al63, which concluded that the weight of evidence suggested
only sporadic, limited neurocognitive damage from conformal radiotherapy at the usually prescribed
doses for LGG. The limited prospective data available63-66 show only minor cognitive effects
attributable to radiotherapy, although there is a lack of data beyond five years post-radiotherapy. This
deficiency is being addressed by the current EORTC prospective study, but results will not be
available for some years.
7.4.2
Chemotherapy
The case for chemotherapy in the adjuvant setting is not currently established for LGA. Although
responses have been seen with a variety of regimens–CCNU, PCV, temozolomide67-70–in small
studies in the setting of recurrence or pre-radiotherapy, studies in which chemotherapy has been added
Low-grade astrocytomas
79
to radiotherapy have not demonstrated additional benefit. A small trial conducted by the Southwest
Oncology Group (SWOG)71 randomised patients to radiotherapy alone (55Gy, n=19) or to
radiotherapy plus CCNU (n=35). This trial was stopped early due to lack of accrual, however, there
was no significant difference in median survival or response rate between the two treatment arms.
Similar results were seen in the randomised trial RTOG 9802,72 in which 251 patients with
unfavourable features (age ≥40 years, subtotal resection/biopsy) were randomised to either RT alone
(54Gy) or RT plus six cycles of PCV chemotherapy. There was no improvement in overall survival
with the addition of PCV to RT; the chemotherapy arm did demonstrate a significant benefit in
progression-free survival, but was also associated with significantly more acute treatment toxicity. A
direct comparison of radiotherapy and chemotherapy in the adjuvant setting has not been previously
undertaken, but this is currently being investigated in the EORTC study 22033/26033 (RT versus
temozolomide).
Key point:
•
When no other treatment can be offered and there is clear clinical and/or radiological
progression, there is definitely a role for radiotherapy. In the post-surgical setting, its role is
less well defined. If surgery offers relief of symptoms and halts progression, then adjuvant
treatment can be reserved for progressive disease. If radiotherapy is given immediately
after surgery, it will extend TTP but will not extend OS any longer than if given later when
the disease progresses. The role of chemotherapy in the treatment of LGAs is unclear.
7.4.3
Prognosis
LGAs have a wide spectrum of outcome, but generally have a period of relative stability for four to
seven years before a period of accelerated growth, usually associated with transformation to highgrade astrocytoma.60 Survival following accelerated growth averages 12 months. Over the past three
decades, survival for low-grade astrocytomas has increased.73
Favourable prognostic factors include age less than 40 years, seizures as presenting symptom, good
performance status and absence of contrast enhancement, with median survival ranging from as little
as 12 months for patients aged over 40 years with poor performance status to 128 months for patients
aged under 40 years with good performance status.74 Contrast enhancement confers a worse prognosis
as it is more commonly associated with high-grade gliomas and suggests transformation and more
rapid growth.
The EORTC reported the largest patient data set to determine prognostic factors for patients with lowgrade gliomas (EORTC 22844 and 22845). Three hundred and twenty-two patients in EORTC 22844
were analysed to determine independent prognostic variables, which was subsequently validated on
the 288 patients from EORTC 22845 (Table 7.1).75 Determining an individual’s prognosis and
estimated time to malignant transformation is crucial to decision-making about timing of intervention
versus observation.
Loss of 1p/19q is rare in LGAs, as compared with oligodendrogliomas. Approximately 60% of lowgrade astrocytomas have an alteration of the p53 tumour suppressor gene, and although some studies
have reported a less favourable prognosis in patients with p53 mutations, results have been
conflicting.76 There does not appear to be an association between p53 status and response to therapy.
80
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Table 7.1
Prognostic variables for low-grade gliomas
Characteristic
Age, years
Largest diameter of
the tumour
Tumour crossing
midline
Histology
Neurologic deficit
Score (sum of above
factors)
Hazard ratio
<40
1
>40
1.26
<6cm
1
>6cm
1.23
No
1
Yes
1.37
Oligodendroglioma /
mixed glioma
1
Astrocytoma
1.3
Absent
1
Present
1.35
0
Median survival (years)
9.2
1
8.8
2
5.8
3
3.5
4
1.9
5
0.7
Adapted from Lang75
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65
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74
Bauman G, Lote K, Larson D, Stalpers L, Leighton C, Fisher B et al. Pretreatment factors
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75
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24(8):1236-1245.
76
Okamoto Y, Di Patre PL, Burkhard C, Horstmann S, Jourde B, Fahey M et al. Population-based
study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and
oligodendrogliomas. Acta Neuropathologica 108(1):49-56, 2004.
Low-grade astrocytomas
87
8
HIGH-GRADE ASTROCYTOMAS
8.1
Introduction
High-grade astrocytomas are the commonest type of brain tumour and are a major cause of morbidity
and mortality in middle age and in the elderly. Long-term survival is rare.
Tumours of neuroepithelial origin account for more than half of all brain tumours, and more than 50%
of these are high-grade astrocytomas. These tumours occur most commonly in the sixth to eighth
decade of life and are slightly more common in males than females.1–3 In Australia, there are more
than 1300 primary brain tumours diagnosed each year.4 In 2004, there were 1369 central nervous
system (CNS) tumours, with 1080 deaths.
The prognosis for high-grade astrocytoma is very poor, with little change in survival since the 1980s5,6
despite some incremental improvements in multimodality therapy.7 The overall survival to two and
five years is 36% and 28% respectively, and for the most malignant forms, average survival is
generally less than 12 months, with only 3% of patients surviving to two years.2 Patients eligible for
chemo-radiotherapy have a better outlook with two-year survival of 26.5%.7 Prognosis is worse for
higher-grade histopathology, increasing age at diagnosis, poor performance status at presentation and
possibly, residual disease after surgical resection.9–17
8.1.1
Causes and risk factors
There are currently few well-defined causes or known risk factors for high-grade astrocytoma,
although both genetic and environmental factors have been suggested.18,19 A minority of cases are
associated with rare hereditary syndromes or therapeutic radiation. Of the genetic syndromes, LiFraumeni syndrome, a germline mutation of p5320, neurofibromatosis types 1 and 2, Turcot syndrome,
tuberous sclerosis and Ollier disease, account for a fraction of all cases.19 Prior exposure to
therapeutic doses of ionising radiation is known to be associated with later development of high-grade
astrocytoma.21,22 Exposure to environmental and dietary factors, and most recently, mobile telephone
use, have all been suggested as risk factors and publicly debated. However, there is no clear evidence
or consensus.19,23–26 (For more information see Chapter 1 Setting the scene.)
8.1.2
Presentation and diagnosis
The clinical presentation of high-grade astrocytoma depends on the tumour location and rate of
growth. They occur most commonly in the cerebral hemispheres and are less common in the posterior
fossa and brainstem.27–29 Presentation is most commonly with generalised symptoms, including
headache and cognitive dysfunction.30 Seizures are the second-most common presentation and the
incidence of seizures is between 40% and 80% with an inverse relationship to tumour grade.31,32 Focal
neurological deficits are related to location of the lesion in the brain. Presentation with sudden
symptoms due to haemorrhage is unusual33–35 and symptom onset usually occurs over weeks to
months.27,28
Initial investigation of high-grade astrocytoma is largely based on neuro-imaging. While imaging
technology has advanced rapidly in recent decades, with increasingly accurate prediction of tumour
type and extent, neuro-imaging cannot conclusively confirm the histological diagnosis or predict
disease behaviour.36,37 The modality of choice is contrast-enhanced magnetic resonance imaging
(MRI), although computed tomography (CT) is often the first investigation performed due to cost and
availability. The typical MRI appearance of high-grade astrocytoma is a hypo-intense or mixed
density mass on T1-weighted images with heterogeneous or ring-like enhancement with contrast, but
findings vary widely.38–40 Signal abnormalities on T2-weighted and fluid-attenuated inversion
recovery (FLAIR) images show oedema surrounding the central tumour mass. Oedema may be
88
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
extensive, and also indicate infiltrating tumour cells, however tumour infiltration may extend beyond
the imaging borders of the tumour.41
A number of newer neuro-imaging modalities are being investigated for more accurate prediction of
histology, tumour recurrence, and treatment response, including magnetic resonance spectroscopy
(MRS).42–44 Diffusion-weighted MRI (DWI) and diffusion tensor imaging (DTI) may have the
capacity to improve anatomic delineation of the tumour for treatment45–51 and improve prediction of
tumour grade52 (see Chapter 5 Imaging).
8.1.3
Classification, histopathology and molecular biology
High-grade astrocytomas include WHO grade III (anaplastic astrocytoma [AA]) and grade IV
(glioblastoma multiforme [GBM]) tumours.53,54 Classification into grade has prognostic significance
and is based on histological features. These divisions are descriptively useful but at times somewhat
artificial. Immunohistochemical detection of antigens associated with cell division including Ki-67,
may be used as an adjunct to determine a �proliferative index’ which correlates with histological grade
and prognosis.55–59
Increasingly, molecular rather than histological descriptions and correlations are being sought for
astrocytoma.60,61 These are aimed at more accurately understanding tumour biology and predicting
behaviour and treatment response.62–65 It is becoming increasingly clear that histologically similar
tumours may have distinct molecular phenotypes.60,66,67 It is unclear whether these differences relate
to the cellular origin or molecular genesis of the tumour or are a signature of different mechanisms of
tumour progression.68 Greater understanding of the biological, genetic and molecular characteristics
of the central nervous system has led to a number of new hypotheses, including origin from stem cells
or glial precursor cells and dedifferentiation from mature glial cells.69–73
Thus, recent advances in the genetics and molecular biology of cancer have led to a revolution in our
understanding of high-grade astrocytoma. Simple classifications based on clinical, imaging and
histopathological parameters are being superseded by increasingly complex descriptions of this
heterogeneous group of tumours. This is best illustrated by the understanding that tumours with
common histopathology actually comprise distinct molecular subtypes, typified by primary and
secondary GBM (see below). Classification schemes have been largely based on the concept that
astrocytomas show an inherent tendency to progression to a more malignant phenotype, and tumours
have been morphologically categorised into the histopathological grading schemes described in
chapter 6 Diagnosis and pathology.68,74,75 Further investigation has shown that this progression is
associated with the sequential acquisition of genetic alterations. These include initially, mutations in
the TP53 gene and homozygous deletions of the p16 tumour suppressor genes and later, loss of
heterozygosity (LOH) on chromosomes 10 and 19q and amplification of the epidermal growth factor
receptor (EGFR). However, not all tumours have this molecular phenotype and two pathways are now
defined.76–78
8.1.4
Primary and secondary GBM
Primary GBM appear to arise de novo with no precursor lesion and occur in older patients.53,76,77 The
most common abnormality found is amplification of EGFR77,79, with a low rate of TP53 gene
mutation.78 In addition, primary GBMs have a high frequency of loss of the long arm of chromosome
10.77,79–81
Secondary GBMs are thought to progress from lower-grade tumours by the pathway described above,
and commonly occur in younger patients. The most common molecular abnormality in these tumours
is mutation of the TP53 gene78,82, which is seen in 30–50% of astrocytomas of all grades.57,83–85
Both low- and high-grade astrocytomas are characterised by gains on chromosome 7.86,87 The primary
and secondary GBM pathways are not mutually exclusive and possibly interact. For instance, a GBM
High-grade astrocytomas
89
with TP53 mutations may also have a minority of cells with amplified EGFR, however, the TP53
phenotype seems to inhibit widespread amplification of EGFR.84,88 Thus, there is molecular
heterogeneity within the two broad subtypes. A number of key pathways lead to the phenotype of
malignant astrocytoma, with uncontrolled cell proliferation and survival, angiogenesis and invasion.
8.2
Management of high-grade gliomas
The management of high-grade gliomas may involve surgery for biopsy or debulking, radiotherapy,
chemotherapy or a combination of treatments. In some circumstances treatment may not offer a
benefit in survival or quality of life and should not be offered. Management decisions are complex
and usually involve the patient, carer and several professional groups. The approach to decision
making is discussed in Chapter 2 Approach to the patient.
8.2.1
Surgery
Tissue diagnosis in patients with high-grade astrocytoma suspected prior to commencing definitive
treatment
There are no studies definitively demonstrating improved or similar outcome in patients with highgrade astrocytoma in whom a tissue diagnosis is obtained compared to those in whom there is
diagnosis based on clinical or imaging criteria only. However, the following considerations are
relevant.
A single retrospective study of 82 older patients (age 62–99) with suspected primary brain tumour on
CT scan, showed that the 37 who were biopsied lived longer than those who were not (median
survival 81 versus 47 days). However, there was strong selection bias for biopsy of younger and fitter
patients, and treatments varied.89
Evaluations of CT, MRI and newer imaging techniques for accuracy in diagnosis of suspected highgrade astrocytoma, and differentiation from other tumours and non-tumour lesions, show variable
sensitivity, specificity and positive and negative predictive value ranging from 50% to 100%
depending on the study, which is not sufficient for a definitive diagnosis of tumour type or grade.90–100
Most studies have compared imaging diagnosis with histological diagnosis, but vary in quality in
terms of rigour of imaging quality control and experience of observers. However, overall, definitive
diagnosis of lesion type and grade cannot be made on imaging alone.
There is no evidence to favour a particular biopsy technique, but observational studies have shown the
mortality of biopsy to be 0–3% and morbidity 0–13%, with a diagnostic yield of 89–100%.101–112
Retrospective comparisons favour image-guided over free hand biopsy but there are no randomised
comparisons.113,114
Recommendations
Level
References
A tissue diagnosis should be obtained in all patients with a
suspected high-grade astrocytoma before commencing
definitive treatment.
III
115
Anti-neoplastic treatment should not be offered without a tissue
diagnosis unless biopsy is considered too dangerous.
III
90–100
Effect of tumour resection, as compared with biopsy alone, on outcome for patients with high-grade
astrocytoma
The evidence for an improvement in outcome with surgical resection for patients with high-grade
astrocytoma, reviewed below, is scant and often of poor quality. Given that the majority of expert
90
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
opinion has favoured maximal tumour resection over the past three decades, additional reasons, other
than improvement of survival, have often been given to support resection of tumour over biopsy.116,117
These include:
•
More accurate diagnosis, particularly of tumour grade, with the larger specimen of surgical
resection as compared with the small specimens of biopsy, which are subject to sampling
error.116,118–120 (see Chapter 6 Diagnosis and pathology)
•
Reduction of mass effect with improvement of symptoms and thus quality of life and better
tolerance of adjuvant therapy and reduction of corticosteroid requirements.121–123
•
Cytoreduction, which may have an oncological advantage and prolong survival sufficiently for
adjuvant therapy to proceed. Additionally, surgery is the only cytoreductive therapy that not only
kills, but also removes cells, which is of importance intracranially, and for which there is limited
physiological capacity.
•
Provision of tumour for research and analysis.
However, the quality of evidence that these aims are achieved is in general no better than for outcome
in terms of survival, functional status or quality of life.
The effect of resection on outcome for patients with high-grade astrocytoma has been reviewed
regularly, including recently by the UK National Institute for Health and Clinical Excellence in
2006.124 They identified fourteen relevant studies: three systematic reviews, one randomised
controlled trial and ten observational studies. A review of the subsequent literature revealed no
relevant studies.
There is no high-quality evidence to suggest better outcomes from surgery over biopsy for patients
with high-grade astrocytoma. A systematic review of randomised controlled trial evidence for The
Cochrane Library125 found one small trial that showed a modest but significant survival benefit
following resection compared with biopsy in elderly patients. The study had significant
methodological problems, particularly as only 23 of the 30 patients ultimately had an astrocytoma and
it was underpowered.126 This review concluded that resection could not really be supported. A similar
review in 2004 suggested a statistically significant survival benefit for resection over biopsy but
cautioned about the quality of the evidence, particularly selection bias.127 An older review of nonrandomised, largely retrospective studies reached the same conclusion but commented that there may
be a subgroup of young patients who benefit from resection.12
Observational study evidence reaches no consensus.11,128–130 The major methodological flaws of these
retrospective studies are strong selection bias, incomplete data and quantification of extent of
resection by inaccurate intra-operative assessment rather than post-operative imaging.131 However, a
number of these studies comparing biopsy with resection suggest a survival benefit for those
undergoing surgical resection132, including a recursive partitioning analysis of the literature for highgrade astrocytoma.133 An analysis of patients in the Glioma Outcomes Project showed prolonged
survival with tumour resection rather than biopsy. There was a strong selection bias for resection for
younger patients with better performance status and unilateral, unifocal lesions. However, if patients
aged over 65 years, those with a Karnofsky Performance Status (KPS) less than 70 and those with
multifocal or bilateral tumours were excluded, the survival advantage persisted (p = 0.0015).14
In another analysis of 565 patients from the Glioma Outcomes Project data, GBM and AA were
considered separately. For both there was significantly better survival for resection compared with
biopsy. For AA this was 87 versus 52 weeks and for GBM 45 versus 21 weeks. This analysis was
adjusted for age, KPS and multifocal or bilateral disease.13
High-grade astrocytomas
91
Recommendation
Level
References
Patients with high-grade astrocytoma should have surgery for
tumour resection if safe as this extends survival when compared
to biopsy alone.
II
125,126
Effect of extent of tumour resection on outcome for patients with high-grade astrocytoma
As for surgical resection compared to biopsy alone discussed above, the evidence that extent of
resection affects outcome is limited. A Canadian 2004 systematic review examined outcome after
gross total tumour resection compared to subtotal or partial resection in malignant glioma.127 They
included five retrospective and five prospective studies, all of which suggested improved survival
after gross total resection compared to subtotal or partial resection. There was likely to be significant
selection bias, with younger, better performing patients being chosen for more extensive resection.
However, this observational study evidence is suggestive of an advantage in terms of survival
following gross total resection over partial resection.
Recommendation
Level
References
Patients with high-grade astrocytoma should have surgery for
maximal tumour resection, aiming for gross macroscopic
resection if safe, as this extends survival when compared to
biopsy, subtotal or partial resection.
II
127
Effect of tumour resection on outcome in older patients (over 65 years) or those with poor
performance status with high-grade astrocytoma
The evidence for improvement in outcome with resection in GBM patients with the poorest prognosis,
that is, the elderly (age >65) and those with poor performance status (KPS <70) is scanty. In general,
these patients are either excluded from studies or are included in the biopsy-only group, thus there is
strong selection bias. However, the only randomised controlled trial of biopsy versus resection in
GBM was conducted in elderly patients over the age of 65. This small trial showed a modest but
significant survival benefit following resection compared with biopsy in elderly patients but had
significant methodological problems.126
In older or poorly performing patients there may be significant concerns regarding fitness for surgery.
Recommendation
Level
References
Patients with high-grade astrocytoma who are over the age of 65
or have poor performance status should have surgery for tumour
resection if they are fit for surgery, as this extends survival when
compared to biopsy alone.
II
126
Effect of local chemotherapy (carmustine wafers) on survival for patients with high-grade
astrocytoma
Systemic chemotherapy for brain tumours has been hampered by difficulty achieving adequate
exposure to intracranial tumour with systemic administration without general toxicity. This effect is
primarily due to the effectiveness of the blood–brain barrier. To overcome this problem, local delivery
systems have been proposed, the most widely accepted being implantable chemotherapy wafers.134,135
Since 1987, clinical studies have demonstrated a role for implantable carmustine polymer wafers
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
(GliadelВ®) for the delivery of high local chemotherapy concentrations136 to the tumour cavity after
surgical resection.
Efficacy was first tested in recurrent high-grade glioma in patients who had already undergone
maximal treatment, many with multiple craniotomies, radiotherapy and chemotherapy. In a 1995
prospective randomised phase III trial of 222 patients137 there was an improvement in average survival
from 23 weeks after repeat surgery to 31 weeks with carmustine wafer implantation. Mortality at six
months for the GBM subgroup was decreased from 64% to 44%. In a subsequent case-control,
retrospective study with 62 patients138, no survival advantage was demonstrated.
Efficacy was then tested in newly diagnosed high-grade glioma. A 1997 randomised, prospective
phase III trial with 32 patients139 demonstrated an improvement in survival from a median of 40
weeks to 58 weeks after primary surgery, wafer implantation and radiotherapy as compared to surgery
and radiotherapy alone. This study had relatively small numbers in both arms and had a mix of
tumour types in the treatment arm and only GBM in the placebo arm. When only GBM was analysed
against the placebo group, there was a significant survival advantage in the treatment arm but less
than seen when mixed pathologies were included.
A larger prospective randomised multi-centre phase III trial by Westphal et al of 240 patients in
2002140 demonstrated an improvement in median survival from 11.6 months to 13.9 months. This
effect remained following adjustment for factors affecting prognosis and in subgroup analysis.141 This
study, however, had strict inclusion criteria and included younger neurologically-well patients who
survived longer than average, even if they received placebo, than the usual cohort of patients with
high-grade astrocytoma. A subsequent study suggested that only 25% of patients with an initial
diagnosis of high-grade astrocytoma would be eligible for entry into that phase III trial and thus it was
not reflective of all patients.142
Long-term follow up of the Westphal et al study143 published in 2006 concluded that the survival
benefit extended to two- and three-year endpoints in a statistically significant fashion. The GBM
subgroup did not achieve statistical significance, however when integrated with the earlier phase III
study by Valtonen139, a statistically significant survival advantage was demonstrated.
There have been concerns about complications resulting from carmustine wafer implantation. Brem et
al, in the 1995 placebo-controlled phase III prospective study of 222 patients, demonstrated no
clinically important local or systemic side effects from the implanted 3.85% carmustine wafers.144
Reported complications of seizures (19%), cerebral oedema (4%), poor wound healing (14%) and
infection (4%) did not achieve statistical significance between the study and control groups. In the
1997 randomised prospective study of 32 patients at primary resection of high-grade astrocytoma139,
ten serious complications were identified in five of sixteen patients in the carmustine group compared
with five serious complications in four patients of the control cohort. This study concluded that there
was a higher incidence of complications in the carmustine wafer group. These findings were also
observed in the retrospective study by Subach et al.138 They found higher rates of CSF leak, wound
dehiscence, meningitis and brain abscess in the carmustine wafer implantation group in recurrent
GBM. Local complications are dependent on the carmustine dose in the wafer. Olivi145 and Westphal
et al140 reported higher rates of both CSF leak and intracranial hypertension in the carmustine wafer
treated patients with newly diagnosed high-grade astrocytoma. Another study of 46 patients treated
with primary carmustine wafer implantation at surgery for newly diagnosed high-grade astrocytoma
and subsequent standard external beam radiotherapy concluded that the radiotherapy is acutely well
tolerated, however caution needs to be exercised during reduction of dexamethasone dose due to
rebound cerebral oedema.146 They also suggested difficulties in assessing tumour recurrence on MRI
after wafer implantation due to local necrosis and advised caution, but this was not the finding of all
authors.147
The National Institute for Health and Clinical Excellence (NICE) in the UK reviewed the evidence
regarding carmustine wafers, reported in 2007. Based on FDA and manufacturer re-analysis of the
High-grade astrocytomas
93
RCT data, they reported that carmustine wafers are effective for prolonging median survival but not
progression-free survival in newly diagnosed high-grade astrocytoma. However, they determined that
they should only be used in patients in whom 90% or more of the tumour had been resected.148 This
was based on a subgroup analysis showing this group to have the greatest survival benefit with
carmustine wafers (median survival gain of 2.2 months over placebo), with no effect being seen in
patients in whom lesser tumour resection was achieved. The difficulty of determining extent of
resection intra-operatively was acknowledged.
The role of carmustine wafers in combination with concomitant temozolomide and radiotherapy, other
systemic chemotherapy and radiotherapy is undergoing evaluation149–151, but there is no evidence for
efficacy or safety of concurrent carmustine and temozolomide. Carmustine wafers have not been
compared directly with temozolomide as regards efficacy and safety (see section 8.2.3
Chemotherapy). The current Pharmaceutical Benefits Scheme provisions for carmustine wafers and
temozolomide prevent the subsidy of both agents at diagnosis. The use of these agents should be
planned by a multidisciplinary team.
Recommendation
Level
References
Patients with high-grade astrocytoma benefit from implantation
of carmustine wafers at the time of surgical resection of tumour
as they provide a modest survival benefit of 8 to 11 weeks.
I
139 141
Effect of resection of recurrent tumour on outcome for patients with high-grade astrocytoma
Despite recent advances that have led to some standardisation of initial treatment of high-grade
astrocytoma, currently there is no standard for treatment of the inevitable recurrent tumour.
Recurrence may be defined as either radiological (asymptomatic) or clinical (symptomatic) evidence
of new or enlarging tumour. This is often poorly defined in the literature discussed below, as is the
timing of treatment, that is, whether symptomatic or radiological recurrence was treated. Practices
varied widely but the main indication for a second operation was to postpone the onset of neurological
symptoms and reduce the tumour bulk prior to further therapy. Thus many authors recommend reoperation in the asymptomatic or mildly symptomatic patient.152,153 One study of 231 prospectively
evaluated high-grade astrocytoma patients enrolled in other treatment trials reported that median
survival of patients with asymptomatic radiological progression was significantly longer (42 weeks)
than that of symptomatic patients (13 weeks).154 Multivariate analysis revealed that more aggressive
treatment of asymptomatic patients with surgery and second-line chemotherapy was the most
important prognostic variable.
Differentiation of treatment effects–particularly radiation necrosis, but also the effects of
chemotherapy–from tumour progression or recurrence is important and is discussed in Chapter 5
Imaging.
The stated indications for and aims of surgery in the management of recurrent high-grade astrocytoma
are similar to those at the time of initial presentation.155
These include:
•
Accurate histological diagnosis, particularly if the original tumour was of lower grade, but also to
exclude radiation necrosis or to re-evaluate the tumour at the molecular level.
•
Reduction of mass effect with improvement of symptoms, better tolerance of adjuvant therapy
and reduction of corticosteroid requirements.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
•
Cytoreduction, which may have an oncological advantage and prolong survival sufficiently for
adjuvant therapy to proceed. Additionally, surgery is the only cytoreductive therapy that not only
kills but also removes cells, which is of importance intracranially, and for which there is limited
physiological capacity.
•
Provision of tumour for research and analysis.
A review of the modern English literature regarding surgery for recurrent high-grade astrocytoma
yields 20 papers.123,152,153,156–172 Overall, the quality of the evidence for an effect of resection on either
length or quality of survival for recurrent high-grade astrocytoma is poor. The literature is
characterised by strong selection bias, incomplete data and quantification of extent of resection by
inaccurate surgeon estimate rather than post-operative imaging.131 The selection bias is largely related
to the choice of patients who are younger and fitter for surgery.
There has been no systematic review of the literature regarding efficacy of resection for recurrent
high-grade astrocytoma. Of 17 studies that report survival with reoperation152,153,156,157,159–166,168–170 four
analysed prospectively collected data and the remainder were retrospective reviews. There are no
randomised studies and a small number of low-grade tumours were often included in the study group.
There was no significant difference in survival between the prospective and retrospective studies. The
average age of the more than 750 patients in these studies was 50 years. This young cohort suggests
selection bias for younger, and presumably fitter, patients for re-operation and many studies
concluded there was a survival benefit, particularly for young fit patients. However, overall the
average survival from diagnosis in re-operated GBM patients in these studies was 60.5 weeks, which
is similar to that of best standard of care.7 Based on the available literature, it cannot be concluded that
surgery for recurrent high-grade astrocytoma increases survival. However, the consensus amongst
authors is that, in selected patients, surgery may improve quality of survival.156,161–166,168
The risks of re-operation for recurrent high-grade astrocytoma are an important consideration in these
often disabled and immunocompromised patients with limited survival, although not all studies
include mortality and morbidity data. Reported mortality ranges between 0 and 17%. Eighteen of the
studies described above reported mortality. The average mortality of more than 800 patients
undergoing re-operation was 3%.123,152,153,156,158–170,172 If two studies with very high mortality (17% and
11%)161,172 are excluded, mortality was 1.6%. Twelve of these 18 reports also reported morbidity, with
an average of 16%.123,152,158,160,162–165,167,169,170,172 If the studies of Young et al172, Fadul et al123 and
Chang et al158 are excluded, morbidity was 7.6%. These three studies report morbidity rates of greater
than 25%. Two of the three studies reporting high morbidity are prospective, thus the morbidity data
may be more accurate and the reported morbidity of retrospective studies is likely to be an
underestimate. These results are comparable to carefully documented, reported, generally accepted
mortality and morbidity after craniotomy for any intra-axial tumour.122
Thus it may be concluded that surgery for recurrent high-grade astrocytoma carries minimal
additional risk when compared to initial craniotomy. However, the reports of re-operation for
recurrent high-grade astrocytoma favour young fit patients and probably under-report complications.
One prospective study comparing first and second craniotomy for high-grade glioma found a higher
rate of perioperative complications for second craniotomy, particularly neurological worsening and
infection.158 A higher infection risk after second craniotomy was also found in one other large
prospective study.173
Recommendation
Level
References
Patients with recurrent high-grade astrocytoma, particularly
younger, asymptomatic patients, may benefit from resection of
tumour.
III
156,161–
166,168
High-grade astrocytomas
95
Minimum safety requirements for centres to perform surgery for patients with high-grade
astrocytomas
Currently, neurosurgery for high-grade astrocytoma in Australia is performed in tertiary referral
public hospitals and selected private hospital facilities with established neurosurgical staff and
expertise.
In most instances, minimum safe requirements for neurosurgery in a particular centre are based on
consensus and statutory regulations rather than evidence, which is rarely available. General
considerations for the operating room include:
•
Neurosurgery should be performed in a facility accredited through assessment by the Australian
Council on Healthcare Standards (ACHS) (<www.achs.org.au>).
•
Basic standards for operating rooms encompass numerous policy documents and regulations from
Standards Australia (<www.standards.org.au>), State and Federal government, specialist medical
colleges and the Australian College of Operating Room Nurses (ACORN).
•
Provision of sterile equipment is an essential standard of neurosurgical care and is governed by
Australian Standard AS/NZS 4187:2003 (<www.standards.org.au>). The maintenance of sterility
of personnel and materials during surgical procedures is covered by ACORN Standards 2006 as
are other standards of nursing roles, competency and continuing education (www.acorn.org au).
•
NSW Department of Health Policy Directive TS10 �Standard Procedures for the Handling of
Accountable Items in the Operating Suite and other Procedural Areas’ (and other applicable State
Government regulations) governs surgical counts during procedures
(<www.health.gov.org.au/policies/>).
•
The Australian and New Zealand College of Anaesthetists (ANZCA) recommends minimum
standards with regards to provision of a safe anaesthetic in Technical Professional Document T1
�Recommendations on Minimum Facilities for Safe Administration of Anaesthesia in Operating
Suites and Other Anaesthetising Locations – 2006’. This, and more than 50 other Professional
Documents and recommendations, are available on the ANZCA website
(<www.anzca.edu.au/resources/professional-documents>).
Recommendation
Level
References
Surgery for patients with high-grade astrocytomas should be
conducted in accredited facilities complying with all relevant
State, Federal, professional and educational policies, standards
and guidelines.
III
156,161–
166,168
In addition to a standard safe operating room, it would be generally agreed that centres conducting
surgery for high-grade astrocytoma should have:
•
On-site, 24-hour neuroradiology including CT, MRI and angiography, with experienced
neuroradiology staff. Facilities should not be so physically removed from the main location of
patient care so as to present an unreasonable danger to patients during transportation.
•
An on-site intensive care unit (ICU) able to provide complex, comprehensive pre- and postoperative care. The Joint Faculty of Intensive Care Medicine of ANZCA gives recommendations
for minimum standards for ICU and other policies
(<www.jficm.anzca.edu.au/publications/policy/>). ICU staff with neuro-intensive care experience
is recommended.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
•
A multidisciplinary team including, in particular, neurologists, radiation and medical oncologists,
neuropathologists, neuroscience nurse specialist and allied health professionals and also general
physicians for expertise and assistance in the peri-operative period. Specialty surgical services,
including plastic and reconstructive surgery or otorhinolaryngology are also occasionally essential
for high-grade astrocytoma surgery and should be available.
Recommendation
Level
References
Surgery for patients with high-grade astrocytomas should be
conducted in a multidisciplinary environment with input from
neuroradiology, intensive care, medical and radiation oncology,
neuropathology, neurology, specialist surgery and nursing and
allied health services.
III
156,161–
166,168
Specialist neurosurgical operating room equipment, the availability of which would generally be
considered mandatory for surgery for high-grade astrocytoma, although not necessarily used in every
operation, would include:
•
facilities to view imaging studies
•
adjustable operating table with adaptation for rigid skull fixation
•
operating microscope
•
stereotactic equipment
•
ultrasonic surgical aspiration device
•
equipment for cortical mapping, including a cortical stimulator and somatosensory evoked
potential equipment174–176
Recommendation
Level
References
Surgery for patients with high-grade astrocytomas should be
conducted in a facility where an operating microscope,
ultrasonic surgical aspirator and cortical mapping equipment are
available.
III
156,161–
166,168
More controversial has been the availability of emerging expensive technologies, particularly in
smaller centres. These include frameless neuronavigation and intra-operative imaging, particularly
MRI. Neuronavigation increases precision and reduces morbidity of surgery by better targeting
surgery on the tumour and uses smaller openings in the skull.
The use of both framed and frameless neuronavigation is now common in centres conducting surgery
for high-grade astrocytoma. Framed systems have historically achieved high spatial localisation and
diagnostic yield. Frameless systems using MRI now offer accuracy comparable to framed systems.177
A comprehensive review of the application and advantages of different systems is beyond the scope of
this document, however, there is some evidence to recommend the use of frameless neuronavigation
for all surgery for high-grade astrocytoma.
A retrospective review of 76 patients compared survival and extent of resection in surgery for highgrade glioma with and without neuronavigation.178 Intra-operative neuronavigation was associated
with significantly improved median survival (from 10 to 16 months) and number of patients with
High-grade astrocytomas
97
gross total resection (from 38% to 64%). There was a non-significant reduction in neurological
deterioration post-operatively in the neuronavigation group. In a large recent retrospective study179 of
486 high-grade glioma patients undergoing surgery, improved outcomes were associated with the use
of neuronavigation, although selection bias with use in younger patients with smaller lower-grade
tumours who presented with a seizure and normal level of consciousness was evident. More patients
were discharged home and hospital stay was shorter. Thus, age and grade accounted for the finding.
Gross total resection was lower in the neuronavigation group.179 A case-control prospective study of
104 patients with GBM in 2000180 showed that intra-operative neuronavigation improved extent of
resection (31% versus 19% gross total resection) with an associated improvement in mean survival
(13 versus 11 months). However, a small prospective, randomised trial of neuronavigation in 45
patients with solitary contrast-enhancing tumours in whom neuronavigation was pre-operatively
judged redundant showed no statistically significant difference in extent of resection or survival. The
authors concluded that neuronavigation should not be considered routine.181
Recommendation
Level
References
Intra-operative frameless neuronavigation improves extent of
resection and survival of patients with high-grade astrocytoma
compared to unguided microsurgery, and its use is
recommended.
III
178,180
Emerging technology
Intra-operative MRI (iMRI) has improved technically in recent years, allowing increasing use of this
expensive technology in centres around the world. The chief intended advantage of this technique as
opposed to intra-operative frameless neuronavigation is avoidance of inaccuracy resulting from intraoperative brain shift. Thus, extent of resection can be maximised and intra-operative complications
minimised.182–187 It is emerging and expensive technology and is not widely available at present.
One prospective study of 40 glioma patients (all grades) has shown an improvement in the gross total
resection rate using iMRI following maximal resection using standard frameless neuronavigation.
Despite the intent, 53% of patients did not have a gross total resection following standard
neuronavigation but further surgery using iMRI achieved gross total resection in all.188 Retrospective
reviews have found similar findings with no increase in operative morbidity.189,190 Despite the
improvement in the extent of resection, a prospective case control study comparing iMRI and
conventional surgery failed to show a survival advantage and operating times were increased by, on
average, two hours.191
8.2.2
Radiotherapy
Effect of radiotherapy on survival for patients with high-grade astrocytoma
This discussion applies to high-grade astrocytoma in general since, particularly in earlier trials, the
distinction between grade III and IV gliomas was unreliably and irregularly reported. The large
majority are assumed to be high-grade astrocytomas (GBM and AA) although other malignant
gliomas may have also been included. Where the distinction between GBM and AA was reported, the
proportion of GBM to AA was typically about ten to one. Radiotherapy appears to benefit GBM and
AA to a similar degree, but the absolute outcomes for AA are far more favourable. For example, the
median survival after conventional radiotherapy for GBM in trial RTOG 7401- ECOG 1374 was 8.7
months compared with 27 months for AA.192
The first randomised trial to demonstrate conclusively that radiotherapy prolongs survival was the
Brain Tumor Cooperative Group (BTCG) trial 69-01. From 1969 to 1972, this four-armed trial
compared different treatment regimens following surgery for malignant glioma.5 Three hundred and
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
three (303) patients were randomised to: supportive care including steroids; whole-brain radiotherapy;
BCNU chemotherapy alone; BCNU chemotherapy with radiotherapy. The radiotherapy dose was 50–
60Gy in 1.8–2.0Gy fractions.
The valid study group comprised 220 patients. The median survival of 14 weeks for the surgery-alone
group was significantly different from that of 36 weeks for those who received radiotherapy.
The Scandinavian Glioblastoma Study Group showed a similar effect of radiotherapy in a controlled
randomised trial starting in 1974.193 After maximal debulking surgery, 118 patients with grade III and
IV supratentorial astrocytoma were randomised to: supportive care; radiotherapy to the whole brain
with a placebo drug; whole brain radiotherapy with bleomycin. The radiotherapy dose was 45Gy
given in 1.8Gy daily fractions. For those receiving supportive care alone, the median survival of 5.2
months was significantly different from that of 11 months for those in the radiotherapy arms.
Other randomised trials have also shown this benefit for post-operative radiotherapy for high-grade
astrocytomas.6,194,195
In a study by Shapiro et al, 33 patients were randomised to receive either intravenous carmustine and
vincristine alone or the same drug regimen plus a radiation dose of 60Gy to the tumour bed.196 This
failed to show a significant survival benefit from radiotherapy though the patient numbers were small
and the performance status of those in the non-radiotherapy arm was better.
Laperriere et al pooled the results of these trials to show a risk ratio for one-year mortality of 0.81
(95% confidence intervals 0.74–0.88) when post-operative radiotherapy is compared to no
radiotherapy following surgery for malignant astrocytoma.197
Recommendation
Level
References
Patients with high-grade astrocytoma should have radiotherapy
because this extends median survival times when compared to
no radiotherapy.
I
5,6,194,195,
198
Effect of delay in initiation of radiotherapy on survival for patients with high-grade astrocytoma
Three studies199–201 have examined the effect of waiting for radiotherapy for high-grade astrocytomas
on outcome. Both studies were retrospective case series, but it would be difficult ethically to perform
a prospective randomised study of the question. Do et al200 reported on 182 grade III and IV
astrocytomas treated with radiotherapy. They found that survival decreased by 2% per day for every
day a patient waited for radiotherapy. Seven patients who were initially thought fit enough to be
offered high-dose treatment died before radiotherapy started. These patients were excluded from the
analysis so the true decrease in survival because of prolonged waiting times is likely to be greater than
was estimated. Burnet199 generated a model of the effects of waiting time from a cohort of 154 Grade
IV astrocytomas treated to 60Gy and compared it with 129 Grade IV astrocytomas treated with
radiotherapy alone as part of a randomised trial. They estimated that grade IV astrocytoma cells
doubled every 24 days and that long-term survival decreased modestly with increasing delay to the
start of radiotherapy.201
Recommendation
Level
References
Radiotherapy should start as soon as possible after a diagnosis of
high-grade astrocytoma is established.
III
202,203
High-grade astrocytomas
99
Optimal total radiation dose and fractionation regimen for patients with high-grade astrocytoma
A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study (RTOG
7401, ECOG 1374) investigated the value of an increased radiation dose to the tumour bed for
patients with high-grade gliomas.192 From 1974 to 1979, 626 patients with high-grade gliomas
underwent surgery and post-operative radiotherapy to a �control’ dose of 60Gy to the whole brain.
Prior to radiotherapy they were randomised to one of the following options: no further treatment; a
boost of 10Gy to the tumour plus a margin; BCNU chemotherapy given concurrently with the control
radiotherapy then adjuvantly; Methyl-CCNU and DTIC chemotherapy given concurrently with the
control radiotherapy and adjuvantly. There was no difference in local control or survival in those
receiving the higher radiation dose. For GBM, the median survival times were 8.7 months for 60Gy
and 7.7 months for 70Gy (p> 0.05). For AA, the survival times were 27 and 36 months respectively
(p>0.05).
A United Kingdom Medical Research Council (MRC) study investigated two different radiotherapy
doses in 474 adult patients with grade III or IV astrocytoma.204 Using a two to one randomisation, 318
patients received 60Gy in 30 fractions and 146 received 45Gy in 20 fractions. The median survival of
12 months in the 60Gy group and nine months in the 45Gy group were statistically different
(P = 0.007).
Walker et al examined the relationship between radiation dose and survival in 621 patients with
malignant astrocytoma entered into BTCG trials 6601, 6901 and 7201 from 1966 to 1975.205
Radiotherapy was given after definitive surgery. The median survivals for those receiving 50, 55 and
60Gy were 28, 36 and 42 weeks respectively. Median survival for the 60Gy group was 1.3 times that
of the 50Gy group (p=0.004).
As a result of these early studies, 60Gy in 2Gy fractions has been accepted as the �standard’
radiotherapy dose and fractionation schedule for high-grade astrocytoma.
Recommendation
Level
References
The standard radiotherapy dose and fractionation schedule for
patients with high-grade astrocytoma is 60Gy in 2Gy fractions
and there is no evidence that higher doses improve outcome.
I
206 208
Effect of alternative radiotherapy fractionation regimens on outcome for patients with high-grade
astrocytoma
The radiotherapy dose that can be delivered to a tumour is limited by normal tissue tolerance. The
tolerance of normal brain using conventional 1.8–2Gy daily fractions is considered to be around
60Gy. For radiobiological reasons, if smaller fractional doses are used, normal late-reacting tissue
tolerance is theoretically increased, while that of acute reacting tissue and tumour remains the same.
This means that giving many small doses (hyperfractionation) may theoretically allow a higher,
biologically effective dose to the tumour without increasing late normal tissue toxicity. Multiple
smaller fractions may also reduce the tumour-protective effects of tissue hypoxia and increase the
chance of irradiating the tumour during a more sensitive part of the cell cycle.
There have been two approaches to alternative fractionation schedules. Hyperfractionation (HF) is
given at the rate of at least two small fractions per day, with several hours between fractions, but the
overall treatment time is the same as for conventional fractionation. The total dose can be increased
while maintaining an acceptable level of complications because smaller doses per fraction are better
tolerated by neural tissue. Accelerated fractionation (AF) refers to a course of radiotherapy where
more than one fraction (of conventional size) is given each day so that the overall treatment time is
shorter than with conventional fractionation. The total radiation dose is usually reduced to keep acute
100
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
toxicity to an acceptable level. The rationale for acceleration is to minimise tumour cell repopulation,
which is likely to increase as the overall duration of the course of treatment increases. Often altered
fractionation schedules involve both HF and AF. The prime intent of these regimens is to benefit
clinically from their radiobiological advantage. However, the shortened overall times of AF regimens
may also be an advantage to patients with poor life expectancy.
Hyperfractionation
RTOG protocol 83-02 was a phase I/II study that investigated the use of HF partial brain radiotherapy
after surgery for high-grade astrocytoma. Fractions of 1.2Gy twice daily to total doses of 64.8, 72,
76.8 or 81.6Gy were used to reducing partial brain fields. In the initial report, survival at the highest
dose appeared worst, approaching statistical significance, while the survival and toxicity profile were
most favourable at 72Gy.209 However, the final report showed little difference between the treatment
arms, and survivals were not significantly different from those in previous series where conventional
fractionation had been used.210
This was followed up by RTOG 90-06, a phase III trial in which 712 patients with malignant gliomas
were randomised to receive either a HF regimen of 72Gy given in twice daily fractions of 1.2Gy or a
conventional regimen of 60Gy in 30 fractions. Initial and reduced partial brain fields were used and
all received systemic carmustine on three consecutive days every eight weeks. There was no survival
benefit from HF, with survival times of 13 and 11 months in the conventional and hyperfractionated
arms respectively (P=0.15). Survivals times were significantly better in the conventional arm for all
patients under 50 years of age and for all patients with GBM under 50.211
Prados et al212 randomised 231 patients with GBM to post-operative partial brain radiotherapy using a
conventional schedule of 59.4Gy in 1.8Gy daily fractions or a hyperfractionated schedule of 70.4Gy
given in twice-daily fractions of 1.6Gy. Half the patients were also randomised to receive the
polyamine inhibitor difluoromethylornithine (DFMO). There was no significant difference in survival
between the conventional and the HF arms.
One study that showed a benefit of HF was that of Shin et al.213 Forty-three patients were treated to
61.4Gy in 69 fractions over 4.5 weeks and 38 patients to conventional treatment of 58Gy in 30
fractions over six weeks. The median survival for the HF arm of 39 weeks was significantly higher
than the 27 weeks for the conventional arm. This was a small study and the survival for the
conventional arm was worse than in other published studies using conventional radiotherapy for highgrade astrocytoma. It has been noted that there was a higher percentage of GBM in the conventional
arm.
Laperriere et al performed a pooled analysis for a systematic review on HF versus conventional
radiotherapy for high-grade gliomas.197 This demonstrated no significant benefit of HF. The risk ratio
for 12-month mortality was 0.89, favouring HF, but the 95% confidence intervals ranged from 0.73 to
1.09.
Accelerated fractionation
Lutterbach et al treated 149 patients with GBM to 54Gy, using three 1.5Gy fractions per day.214 The
median survival of 8.8 months was not an improvement on conventional radiotherapy. EORTC Trial
22803 randomised 340 patients with high-grade astrocytoma to conventional radiotherapy of 60Gy in
30 daily fractions or AF of three fractions of 2Gy each day for five days, a two-week break, then
repeat of the initial five-day schedule.215 Those in the AF arm thus received 60Gy in four weeks
instead of the conventional six weeks. A third arm randomised those in the AF arm to daily
misonidazole. Median and two- and three-year survivals did not differ between the arms. To
investigate whether the two-week gap during treatment contributed to the absence of benefit from AF,
the EORTC Radiotherapy Co-operative Group performed a phase II dose escalation study up to 60Gy
in 30 fractions in 12 days in GBM.216 Again, median survival of 8.7 months for the group did not
represent a survival advantage for these AF regimens.
High-grade astrocytomas
101
The study reported by Werner-Wasik et al210 quoted above in the discussion on HF included an AF
arm of 1.6Gy twice daily to a total dose of 48 or 54.4Gy.210 There were no survival differences
between the treatment arms. Toxicity in the AF arm was low, suggesting scope for dose escalation.
Brada et al217 performed a single-arm study of AF radiotherapy for malignant astrocytomas in 211
patients. The radiation schedule was 55Gy in 34 fractions delivered twice daily. Median survival of
ten months was similar to that of conventional fractionation.
Recommendation
Level
References
For adjuvant radiotherapy for high-grade astrocytoma,
conventional fractionation (single daily fractions of 2Gy) is
recommended. There is no evidence that hyperfractionation
and/or accelerated fractionation improves outcome.
I
218,219
Effect of delivery of a radiation boost by brachytherapy or stereotactic radiosurgery on survival for
patients with high-grade astrocytoma
Brachytherapy and stereotactic radiosurgery both deliver highly conformal radiation to small volumes
of tissue with rapid fall-off in dose outside the treated volume. Considerable dose inhomogeneity may
exist within the irradiated volume. Brachytherapy is further characterised by the risk of bleeding
and/or infection with catheter, seed or balloon placement and a variable dose rate that may affect the
biological effects of treatment. Both treatment modalities have been used for salvage treatment
following malignant astrocytoma progression220,221 and as a means to escalate or boost the dose
delivered with initial therapy (RTOG 93-05).222
Phase II data are available for brachytherapy as monotherapy for low-grade glioma223 and as a boost
for high-grade astrocytoma. Eligible patients are those fit enough to undergo surgery and tend to have
smaller well-defined tumours that are accessible and do not cross the midline. The possibility of any
treatment effect being confounded by patient selection has been raised, although some evidence exists
for a treatment effect within each RTOG recursive partitioning analysis (RPA) class.224
Several studies employing a stereotactic boost are limited by the same caveats in terms of patient
selection.225 A median survival of 96 weeks (actuarial two-year survival of 45%) has been reported by
Sarkaria.226 This study and others also highlight the risk of focal dose escalation, with many patients
requiring ongoing steroid support and an approximate 50% risk of developing radiation necrosis
requiring re-operation.227,228 Further surgical procedures may also confound any benefit seen by focal
dose escalation. A recent systematic review229 of conventional treatment and radiosurgery as a boost,
concluded that no benefit was seen in terms of overall survival, local brain control or quality of life.
Recommendation
Level
References
Focal dose escalation with brachytherapy or stereotactic
radiosurgery as part of initial radiotherapy for patients with highgrade astrocytoma does not improve outcome.
I
230
�Short course’ radiotherapy compared to standard radiotherapy for patients with high-grade
astrocytoma, particularly for those with the poorest prognosis
Full course radiotherapy with concurrent chemotherapy is the treatment of choice for fit patients with
glioblastoma multiforme.7 This section examines the role of short-course radiotherapy for patients
with a poor prognosis.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Predictors of poor survival
There is concern that patients with poor prognosis may undergo long courses of radiotherapy for little
benefit.198 The factors that indicate a poor prognosis include patient age, performance status including
degree of neurological impairment, no history of seizures and extent of surgery.204 There have been
several attempts to develop prognostic indices that categorise patients by their expected survival.
The MRC204 in the UK divided 417 high-grade astrocytoma patients from the first MRC glioma trial
into six groups (Table 8.1) that correlated with prognosis. Patients with a score of 0–15 had median
survival of 51–53 weeks; those with a score of 16–25 had a median survival of 35–41 weeks and
those with a score or 26–28 had a median survival of only 16–23 weeks. A six-week course of
radiotherapy would occupy a significant proportion of the poorest groups’ survival time.231
Other studies have attempted to apply the MRC prognostic scale to their own data. Latif et al232
examined 236 patients treated between 1989 and 1995 and found good agreement. However, 79
patients were excluded because they would not have been eligible for MRC studies because of
performance status or age. Year of referral was also significant, with patients treated in more recent
years having a better survival probability. Akman et al202 used a cohort of 119 patients to compare the
MRC index with a new prognostic index that added tumour size, location and pre-operative and preradiotherapy neurological status to the MRC variables. The MRC groups had significantly different
survival varying from 14 months for scores of 0–15 to eight months for scores of 26–33. Multivariate
analysis showed age and tumour grade were significant. The sample size was small and reduced the
power of the study.
Table 8.1
Medical Research Council (MRC) prognostic index
Factor
Category
Score
Age
<45
0
45–59
6
60
12
Clinical performance status
Extent of surgery
History of seizures
0–1
0
2
4
3–4
8
Complete resection
0
Partial resection
4
Biopsy
8
3 months
0
3 months
none
5
10
Source: MRC 1990103
The RTOG used recursive partitioning analysis (RPA) on the results of its trials to create a dataset of
1578 patients and identified six prognostic groups of high-grade astrocytoma patients (Table 8.2).9
Prognostic factors included patient age, tumour grade, performance status, mental status, neurological
function, extent of surgery and radiotherapy dose. The inclusion of post hoc factors such as
radiotherapy dose reduces the validity and usefulness of the index to provide prospective assessment
of prognosis.
High-grade astrocytomas
103
Table 8.2
Class
Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis
prognostic groups
Age
I
Grade
KPS
50
AA
II
>50
AA
III
<50
AA
<50
GBM
50
GBM
<90
50
AA
70–100
IV
Symptom
duration
(months)
Mental
status
Extent of
surgery
Neuro
deficit
RT dose
Normal
70–100
>3
Abnormal
90–100
3
50
GBM
70–100
PR/CR
No
V
50
GBM
70–100
Biopsy
Yes
50
GBM
<70
Normal
VI
50
GBM
<70
Abnormal
50
GBM
70–100
Biopsy
>54.4Gy
<54.4Gy
AA – Anaplastic astrocytoma (WHO Grade III); GBM – Glioblastoma Multiforme (WHO Grade IV); KPS – Karnofsky
Performance Score; PR – partial resection; CR – complete resection; Neuro – neurological; RT – radiotherapy
Source: Curran et al9
The RTOG model was validated203 on a dataset drawn from subsequent RTOG studies of about 1500
high-grade glioma patients. Median survival ranged from 59 months in Class I, to 4.6 months in Class
VI (Table 8.3). The RTOG partitioning analysis classes accounted for about half of the variance in
survival that was seen in the dataset.
Table 8.3
Survival of Radiation Therapy Oncology Group (RTOG) recursive partitioning
analysis classes
Class
Median survival (months)
Two-year survival (%)
I
59
76
II
37
68
III
18
35
IV
11
15
V
9
6
VI
5
4
Source: Scott et al203
The MRC and RTOG prognostic systems are complex, methodologically flawed and of limited
generalisability because they were derived from patients selected as fit enough to enter clinical trials.
They are also based on old studies from the pre-concurrent chemotherapy era and there is some
evidence of improvements in survival over recent years.206,232 Recently, a simpler prognostic system
has been proposed.207 Patient age and neurological performance status (Table 8.4) were used to define
a favourable and an unfavourable group (Table 8.5).
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Table 8.4
Category
Neurological performance status
Neurological function
0
No neurological deficit
1
Some neurological deficit but fit for work
2
Neurological deficit causing moderate functional impairment
3
Neurological deficit causing major functional impairment
4
No useful function, inability to make conscious responses
Source: Gupta and Sarin207
Table 8.5
Simplified prognostic grouping
Category
Favourable
Unfavourable
Age
Neurological performance status
50 years
0 to 2
>50 years
0 to 1
50 years
3 or 4
>50 years
2 to 4
Source: Gupta and Sarin207
One may conclude from the plethora of prognostic indices that poorer outcome can be predicted by
older patient age, higher tumour grade, and poorer neurological function. However, none of these
variables is predictive in isolation; all of the attempts to generate prognostic indices recognise the
complex interplay of the predictive factors. Good performance status is more predictive of outcome
than age.208 Clinical judgement must weigh up the combination of factors and consider the patient and
their family’s wishes in considering management options for high-grade astrocytomas.
Short course radiotherapy
Many single-arm studies206,208,218,219,231,233–239 have reported the results of short courses of radiotherapy
on selected and unselected patients with high-grade astrocytomas. Selection criteria include age >60,
age>70, poor performance status or poor prognosis MRC or RTOG group. Most studies have
examined total doses of 30–40Gy in 3Gy fractions (range 28Gy in four fractions to 51Gy in 17
fractions). Median survival ranged from four to 13 months. Comparisons with historical controls have
shown similar outcomes to higher-dose regimens but all studies have been small and lack power. Age
alone was not always predictive of poor outcome. Bauman206 reported survival benefit from high-dose
radiotherapy in elderly patients with KPS>50 when compared to short-course radiotherapy. Age did
not predict outcome in patients >70 years208 after adjustment for RTOG prognostic classes. Some
studies218,231,233 reported patients who survived one year or more indicating heterogeneity of tumour
response and the difficulty of reliably determining prognosis.
Four randomised controlled trials have compared radiotherapy dose regimens. The MRC204
randomised 474 adults with grade III or IV astrocytoma to receive 45Gy in 20 fractions or 60Gy in 30
fractions. Patients were aged between 18 and 70 years and their neurological function was �not so
seriously impaired as to make radiotherapy undesirable’. Survival was statistically significantly better
in the 60Gy arm, with a median survival of 12 months, compared with nine months in the 45Gy arm.
A significant improvement in survival with the higher dose was still apparent in the poorest
prognostic group, although the overall survival was worse.
Roa et al240 reported a trial of 100 poor-prognosis patients randomised to receive 60Gy in 30 fractions
or 40Gy in 15 fractions. Patients were >60 years old and had GBM and Karnofsky Performance Status
High-grade astrocytomas
105
(KPS) >50. The study intended to recruit 200 patients but closed after five years when 100 patients
had been accrued. Median survival, health-related quality of life and KPS in each treatment arm were
not statistically different. Another small, randomised trial of short-course radiotherapy for poor
prognosis high-grade glioma patients was reported by Phillips.241 Between 1990 and 1996, 69 patients
were randomised to 60Gy in 30 fractions or 35Gy in ten fractions. All high-grade astrocytoma
patients were eligible except for those <45 years with ECOG performance status 0–2. Median survival
was 10.3 months in the 60Gy arm and 8.7 months in the 35Gy arm, but this difference was not
statistically significant because of the small numbers involved.
A recent randomised study compared 50Gy with best supportive care in patients with GBM who were
70 years or older.242 Eighty-five patients were randomised and the study was stopped at the first
interim analysis because of the significant survival benefit in the treatment arm (29 weeks versus 17
weeks, p= 0.002). Radiotherapy halved the hazard of dying. There were no severe adverse events
related to radiotherapy.
Conclusion
There are groups of patients with high-grade astrocytoma who are unlikely to live for long after their
presentation. The predictors are older age, higher-grade and poorer performance status. The extreme
cases are clear-cut; moribund patients should not be offered radiotherapy because they are very
unlikely to benefit. Very fit patients, regardless of age, should be offered radiotherapy because it may
give them a survival benefit. Patients in the middle ground with older age and mild deficits or younger
age and more severe deficits are much harder to advise. Some will get a survival benefit from
radiotherapy, but the proportion that benefit and the degree of benefit is likely to be reduced.
The evidence base for short-course low-dose radiotherapy is weak. The single institution, single-arm
studies are very heterogeneous and the only conclusion that can be drawn from them is that short
courses are tolerated acutely. One randomised trial confined to patients 70 years and older showed a
significant survival benefit for high-dose radiotherapy when compared with no treatment. The MRC
study is the largest study and showed a benefit for the higher dose even in poor prognosis patients.
The two randomised trials that specifically examined poor prognosis patients were both very small,
accrued slowly and were stopped prematurely because of poor accrual.
Research is needed to determine the role of temozolomide in the poor-prognosis patient group.
Temozolomide prolongs survival when given with a full course of radiotherapy.7 It may be valuable
in poor-prognosis patients either alone as a substitute for radiotherapy or in combination with
radiotherapy.
Recommendation
Level
References
There is insufficient evidence to recommend short-course
radiotherapy.
II
104
Optimal total radiotherapy target volume for patients with high-grade astrocytoma
Randomised controlled trials originally demonstrated an improvement in overall survival when
radiotherapy was delivered to the whole brain (WBRT) following surgical resection of high-grade
astrocytoma.5,6,194
Subsequently, whole versus partial brain irradiation for high-grade astrocytoma was examined by
Shapiro et al.243 In Trial 8001 of the Brain Tumor Cooperative Group, 571 patients with malignant
astrocytoma were treated with radiotherapy plus one of three randomly allocated chemotherapy
schedules. In the earlier part of the trial, all patients received 60Gy WBRT. However, in the later part
they were randomised to receive this same schedule or 43Gy to the whole brain, with a boost to the
106
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
tumour volume of a further 17Gy. There was no statistically significant difference in survival times
associated with the two radiotherapy schedules. This showed that partial brain radiotherapy can be
use, at least for part of the course, thereby potentially reducing neurotoxicity. Furthermore, because
43Gy is unlikely to sterilise microscopic tumour deposits, it is unlikely that inclusion of the WBRT
for part of the treatment would confer any advantage over merely treating the tumour plus a margin
for the entire course.
A review of recurrence patterns by Wallner et al also supports the use of partial rather than WBRT.171
They studied the recurrence patterns in 34 patients who had previously received surgery and
radiotherapy for high-grade astrocytoma. In only two of 34 patients were recurrences multifocal and
78% (25/32) of the unifocal recurrences were within 2cm of the original pre-surgical tumour margin.
A further report by Gaspar et al also documents the failure patterns in 53 patients with recurrent
tumour after previous radiotherapy for high-grade astrocytoma.244 Ninety six percent of these
recurrences were in the brain alone and of those all were within 4cm of the enhancing volume as
defined on the pre-operative CT scan.
Halperin et al reported an autopsy series of unirradiated (or minimally irradiated) patients with GBM
for whom ante mortem CT images were available.245 Hypothetical radiotherapy fields were designed
based on the imaging. The autopsy correlation showed that, in all cases, all detected tumour cells
would have been included in radiotherapy fields, which extended 4cm beyond the peritumoural
oedema.
These data indicate that as the advent of CT and MRI scanning has allowed definition of the tumour
extent, radiotherapy to tumour plus an adequate margin should be used for high-grade astrocytoma, as
WBRT is associated with greater neurotoxicity with no improvement in outcome.
Recommendation
Level
References
For patients with high-grade astrocytoma, post-operative
radiotherapy fields should include the tumour bed with a margin
rather than the whole brain.
II
246,247
Defining target volumes in radiotherapy for patients with high-grade astrocytoma
As described above, reduction of the radiation field to cover the radiologically apparent tumour (socalled involved field radiotherapy [IFRT]) was proposed when analysis of failure patterns following
WBRT demonstrated 70–90% of recurrences occurred within 2–3cm of the original
tumour.171,244,248,249 In addition, sparing of brain tissue would potentially decrease the likelihood of
neurotoxicity occurring as a late sequelae of therapy.
WBRT and IFRT have not been prospectively compared with respect to local control, overall
survival, neurological and neuropsychological outcomes.
Retrospective studies demonstrate equivalent recurrence patterns250–253, local control and a trend
towards better neuropsychological outcomes230 in those receiving IFRT compared to WBRT.
Delineation of an appropriate target volume in IFRT of high-grade astrocytoma is controversial
because of the discrepancy between real tumour invasion and that estimated by CT and MRI.254
Target volume definition is assisted by studies correlating CT and MRI with pathological findings in
untreated patients and studies correlating CT and MRI with patterns of failure following radiation
therapy.
These studies demonstrate that the central low-density tumour area on CT and low intensity area on
T1-weighted MRI corresponds histologically with necrosis, while the surrounding contrast-enhancing
High-grade astrocytomas
107
ring on CT or high-signal intensity region on T1-weighted MRI corresponds to a rim of viable tumour
cells. The area surrounding this rim, which appears hypodense on CT and hyperintense on T2weighted MRI, corresponds to oedematous brain tissue with infiltrating viable tumour cells.255,256
These cells extend throughout a 3cm margin from the border of the necrotic centre defined on CT
scans245,248,255,257 and throughout the hyperintense regions on T2-weighted MRI.256 Isolated tumour
cells beyond these areas have been found in between 25 and 33% of patients.258,259
Similarly, pattern of failure analysis demonstrates that, irrespective of whether WBRT or IFRT is
employed, 70–90% of recurrences occur within 2–3cm of the original tumour site.171,244,248,249 Thus
failure to control the central zone of tumour remains the predominant problem in the radiotherapeutic
management of high-grade astrocytoma.
Based on the available literature, the following option for target volume delineation in high-grade
astrocytoma has been suggested.260 The Gross Tumour Volume (GTV) is defined by the contrastenhanced zone on CT or MRI. The Clinical Target Volume (CTV) encompasses the GTV and the
high-signal area on T2-weighted MRI or the hypodense perifocal zone on CT. The Planning Target
Volume (PTV) is defined by the CTV plus a 5mm margin in all directions. Some authors suggest a
two-phase technique if the CTV is very large (>250cm3), with the boost dose of 10–20Gy delivered to
a target volume defined by the GTV plus a 1cm margin.261
Ideally, target volume delineation should utilise both CT and MRI. The extent of tumour infiltration
or oedema is more clearly defined on T2-weighted MRI than on examination of hypodense areas on
CT.256 Quantitative assessments of the contribution of CT and MRI to composite target volumes
demonstrate that while 50% of the composite CTV is apparent on both MRI and CT, MRI and CT
contribute independently to the volume, with 28% of the composite CTV apparent on MRI only and
21% apparent on CT only.262 As tumour volumes independently apparent on CT and MRI have equal
validity, both imaging modalities should be used in radiation therapy treatment planning for highgrade astrocytoma.
The clinical utility of new imaging modalities (such as PET and MR spectroscopy) in treatment
planning of high-grade astrocytomas is still under investigation.
Recommendations
Level
References
For radiotherapy for high-grade astrocytoma, involved field
radiotherapy provides equivalent rates of local control and
recurrence patterns to whole-brain radiotherapy.
III
230,251–
253,263
The treatment volume or planning target volume (PTV) is defined
as:
III
255
III
256,262
•
clinical target volume (CTV) + 5mm
•
CTV = Gross tumour volume (GTV) + high-signal area on
T2-weighted MRI or perifocal hypodense zone on CT
•
GTV = contrast-enhancing area on CT or T1-weighted MRI
Both CT and MRI should be used for target volume delineation.
Optimal method for differentiating radiation necrosis from tumour progression
Radiation necrosis may lead to neurological dysfunction, oedema and mass effect. The tolerance dose
defined as the 5% complication rate in five years (TD5/5) for partial brain irradiation is about 60 +
10Gy with conventional radiation.264 In actuarial terms, the incidence of biopsy-proven radiation
necrosis increases with time and may be estimated at 5%, 9% and 13% at 12, 24 and 36 months
respectively, with a mean latent interval of 11.6 months. Radiation necrosis is rarely seen below 45Gy
108
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
in 20 fractions (Biological Equivalent Dose of 48Gy in 2Gy fractions) and chemotherapy may be
associated with a fivefold increased incidence compared to radiation alone.265 An increased risk has
been linked to histology, with patients with primary brain tumours more likely to develop necrosis
using focal irradiation than patients with metastases.266
The significance of radiation necrosis lies with the difficulty in distinguishing from progressive
disease. Various strategies, including CT scan and MRI267, including magnetic resonance
spectroscopy and diffusion weighted imaging268, thallium SPECT and PET have all been used with
variable success. Changes seen in imaging may evolve over time and less severe injuries particularly
affecting white matter are frequently demonstrated. PET scanning has been associated with a
sensitivity of 80–90% and a specificity of 50–90%.269 Histology remains the gold standard for
diagnosis, although the subsequent effect on treatment decisions is less clear.270
A number of therapies have been suggested for management. Dexamethasone has been found to be of
most benefit in the early development of radiation injury.271 Steroid requirements were reduced in an
early report detailing vascular endothelial growth factor (VEGF) inhibition using bevacizumab.272
Hyperbaric oxygen therapy has been employed with limited data suggesting a possible role in
children.273 Surgery may be required to treat274 symptomatic mass effect or to avoid the complications
of long-term steroid usage.
Recommendation
Level
References
Histopathology remains the gold standard for diagnosis of
radiation necrosis.
III
271
8.2.3
Chemotherapy
In the more recent chemotherapy trials, AA and GBM are more frequently reported separately. Thus
these tumours will be considered separately unless otherwise stated.
Outcomes of adjuvant chemotherapy after surgery and radiotherapy in patients with glioblastoma
multiforme
A literature search revealed three meta-analyses with similar conclusions. Two earlier meta-analyses,
published in 1989 and 1993, have been criticised for methodological flaws. The meta-analysis
published by the Glioma Meta-analysis Trialists Group in 2002275 identified 3004 patients in 12
randomised trials and used individual patient data (Class IA). In this meta-analysis, 62% of the
patients had GBM. This meta-analysis showed a reduction in the hazard ratio (HR) for death of 0.85
(95% confidence interval (CI) 0.78–0.92). This is equivalent to an improvement in one-year survival
of 6% (95% CI 3%–9%), from 35% to 41%. Mean progression-free survival increased by 1.5 months
(95% CI (0.5–2.5 months), from six months to 7.5 months. Few of the trials incorporated quality of
life data and multiple drugs were used and thus choice of drug is not specified. Review of the
literature since this meta-analysis was performed did not reveal any relevant trials.
Key point:
Adjuvant chemotherapy after surgery and radiotherapy provides modest
improvement in progression-free survival and overall survival for patients with GBM.
High-grade astrocytomas
109
Recommendation
Level
References
Adjuvant chemotherapy alone has been supplanted by
concurrent chemo-radiotherapy followed by adjuvant
chemotherapy and is thus not currently recommended.
II
7
Outcomes of adjuvant chemotherapy after surgery and radiotherapy in patients with anaplastic
astrocytoma
A pre-temozolomide literature review revealed the same three meta-analyses identified for GBM. The
proportion of AA in the Glioma Meta-analysis Trialists Group was 24%.275 Subgroup analysis of the
data showed a similar benefit for AA from the addition of chemotherapy, and an absolute increase in
survival at one year of 5%, from 58% to 63%, and an increase in survival at two years of 6%, from a
baseline of 31% to 37%. Quality of life was not examined.
Literature review of studies completed since this meta-analysis showed no further contributing
studies. There is no quality of life data and the choice of drug is not specified.
Recommendation
Level
References
Adjuvant chemotherapy after surgery and radiotherapy
improves survival and is recommended for patients with
anaplastic astrocytoma (AA).
I
275
Outcomes of concurrent radiotherapy and chemotherapy followed by chemotherapy (Stupp protocol)
in patients with glioblastoma multiforme
The study by Stupp et al7 is the only randomised study that has addressed this question. The study
compared post-operative radiotherapy (60Gy) to post-operative concurrent chemotherapy
(temozolomide 75mg/m2 daily) and radiotherapy (60Gy) followed by six months of temozolomide
(150–200mg/m2 days 1–5 every 28 days for six cycles). Overall, there was a significant improvement
in median survival (12.1 months versus 14.6 months) and two-year survival (10.4% versus 26.5%) in
favour of the chemotherapy arm. There was minimal additional toxicity in the chemotherapy arm.
Recommendation
Level
References
Concurrent radiotherapy and chemotherapy followed by
adjuvant chemotherapy provides a significant improvement in
median and two-year survival in patients with GBM and is
recommended.
II
7
Outcomes of concurrent radiotherapy and chemotherapy followed by chemotherapy (Stupp protocol)
in patients with anaplastic astrocytoma
The study by Stupp et al7 did not include patients with AA. There are no data to recommend this
therapy in these patients and neurological toxicity of combined radiotherapy and chemotherapy in
longer-surviving patients has not been assessed
110
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Recommendation
Level
There are no data regarding either safety or efficacy of
concurrent radiotherapy and chemotherapy followed by
chemotherapy in patients with anaplastic astrocytoma and the
regimen is not recommended.
References
7
Outcomes of concurrent radiotherapy and chemotherapy followed by chemotherapy (Stupp protocol)
in poor performance status patients (ECOG 3-4) with glioblastoma multiforme or anaplastic
astrocytoma
The study by Stupp et al7 did not include patients with performance status of 3 or 4. There are no data
to recommend this therapy in these patients.
Recommendation
Level
There are no data regarding concurrent radiotherapy and
chemotherapy followed by chemotherapy in patients with
performance status 3 or 4 and glioblastoma multiforme or
anaplastic astrocytoma and the regimen is not recommended.
References
7
Outcomes of concurrent chemotherapy and radiotherapy followed by chemotherapy (Stupp protocol)
in elderly patients (over 70 years) with high-grade astrocytoma
The median age of patients on the landmark clinical trial of adjuvant chemoradiotherapy followed by
adjuvant temozolomide for GBM was 56 years, with an age range of 18 to 71 years.7 Patients over 70
years were excluded from the study. Hence, there is no evidence to confirm or refute that patients over
the age of 70 benefit from this regimen.
A small reported case series treated 22 GBM patients over 65 years of age with adjuvant
temozolomide 150 mg/m2 for five of every 28 days with a mean of 4.9 cycles per patient following
surgery and radiotherapy.276 Treatment was adequately tolerated and survival was significantly better
than retrospective comparators receiving surgery and radiotherapy only (median survival 14.9
months). No concurrent combined treatment (radiotherapy with temozolomide) was given in this
series.
Recommendation
As there are insufficient data to make a recommendation for
management with concurrent adjuvant radiotherapy and
chemotherapy followed by chemotherapy in patients over 70
with glioblastoma multiforme or anaplastic astrocytoma,
treatment decisions should be made on an individual basis.
Level
References
277
Outcomes of chemotherapy alone, without radiotherapy in elderly patients (aged over 70 years) with
high-grade astrocytoma
A single-centre phase II study has examined the efficacy of temozolomide without radiotherapy in
elderly patients.278 Thirty-two patients over the age of 70 with histologically confirmed GBM and AA
and an ECOG PS of 2 or better were treated with post-operative temozolomide 150–200 mg/m2/day x
5 q28 days until disease progression. No radiotherapy was allowed on-study. The majority of patients
(n=25) had only a biopsy prior to chemotherapy. A median of four cycles was administered, with a
High-grade astrocytomas
111
median overall survival from diagnosis of 6.4 months and median progression-free survival of five
months. Nine patients (31%) had an objective partial response, and a further 12 patients (41%) had
stable disease as their best response. Fifty percent of patients benefited in terms of an improvement in
KPS, reduction in corticosteroid dose, and/or improvement in Mini Mental State Examination
(MMSE) scores. Safety and tolerability were confirmed in this elderly population (median age 75)
with no treatment-related deaths.
Recommendation
Level
References
Post-operative adjuvant temozolomide without radiotherapy is
safe and tolerable in patients over age 70 with good
performance status. Comparison of outcome with other regimens
has not been made. Treatment decisions should be made on a
case-by-case basis.
IV
278
Outcomes of chemotherapy alone, without radiotherapy in poor-performance status patients (PS3/4)
with high-grade astrocytoma
Radiotherapy or concurrent radiotherapy and chemotherapy for high-grade astrocytoma is of less
benefit to patients with a poor-performance status.7,277 Chemotherapy, particularly well-tolerated
temozolomide, given without radiotherapy may be less toxic and effective as the initial post-operative
adjuvant therapy in these patients. However, there are no reports of clinical trials or retrospective
reviews that directly address this question. Non-randomised data are available on the use of
temozolomide without radiation as initial therapy in elderly patients with GBM. A retrospective
review of 86 consecutive patients identified 32 given temozolomide as an alternative to radiation.279
Temozolomide was well tolerated and survival was not different between radiotherapy and
chemotherapy-alone groups. The KPS was ≤ 70 in 60 patients and a low KPS predicted for poor
outcome. However, among patients with a poor performance status, no comparison of outcomes by
treatment modality (radiotherapy or temozolomide) was reported.
Recommendation
Level
There are no data regarding chemotherapy without
radiotherapy for patients with high-grade astrocytoma and poor
performance status and chemotherapy alone is not
recommended as an alternative to radiotherapy.
References
277
Outcomes of chemotherapy in patients with recurrent high-grade astrocytoma
Many patients with recurrent high-grade astrocytomas are offered chemotherapy; however, the
evidence supporting its use is derived almost exclusively from single-arm phase II studies.
Interpretation of the results of these studies is complicated by a variety of study design factors.
The published clinical data clearly identify chemotherapeutic drugs and regimens that possess modest
activity in recurrent high-grade astrocytoma. Active single agents include temozolomide, carmustine,
lomustine, cyclophosphamide, carboplatin, liposomal doxorubicin, oral etoposide and irinotecan.280–290
In AA, these have resulted in overall response rate (ORR) of 22–34%, six-month progression-free
survival (PFS-6) of 30–49%, median time to progression (TTP) of 4–5.5 months and median overall
survival (OS) of 8–14 months.
The results in GBM are consistently worse, with ORR of 5–20%, PFS-6 of 8–21%, median TTP of 3–
4 months and median OS of 5–7.5 months. Few studies included health-related quality-of-life
112
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
evaluations, but these measures showed improvement (or failure to decline) in association with
objective responses to chemotherapy or progression-free status when reported.281,289,290 A randomised
phase II comparison of temozolomide with procarbazine showed a statistically significant difference
in PFS-6 and median PFS favouring temozolomide, although the median PFS was only prolonged by
one month.289
Toxicity profiles of these agents are variable and the overall excellent tolerability of temozolomide
has contributed to its emergence as the drug of choice for high-grade astrocytoma, despite a lack of
convincing evidence of superior anti-tumour activity. Prolonged schedules (such as seven days
on/seven days off; three weeks on/one week off) have not, however, demonstrated clearly superior
efficacy in phase II clinical trials.291,292
A number of multi-agent chemotherapy regimens have shown activity in relapsed high-grade
astrocytoma. In phase II studies of predominantly or exclusively GBM patients, chemotherapy
combinations have resulted in overall response rate (ORR) of 11–30%, PFS-6 of 29–34%, median
TTP of 3–4 months and median OS of 8–12 months.246,293–297 Randomised trials comparing single
drugs with combination chemotherapy have not been reported in recurrent disease. The decision on
whether to use a multi-agent chemotherapy regimen should also take into account the potentially
greater toxicity of combinations compared to single agents.
The standard of care for initial therapy of GBM has now become post-operative radiotherapy with
concurrent and adjuvant temozolomide, following publication of the phase III trial showing a survival
benefit for this approach compared to radiation alone.7 Since most trials of chemotherapy in relapsed
disease were performed prior to the widespread use of temozolomide in initial therapy, the relevance
of the available data to treatment decisions for current patients with relapsed high-grade astrocytoma
is increasingly difficult to evaluate. Nonetheless, a few studies have enrolled only temozolomide
failures and shown activity with the investigational chemotherapy.283,294
Anti-angiogenic agents have been combined with chemotherapy treatment of recurrent high-grade
astrocytomas. The combination of thalidomide with carmustine was evaluated in a phase II trial which
recruited predominantly relapsed GBM patients exposed to prior chemotherapy.247 The combination
showed modest activity, but potentially contributed to a high rate of thromboembolic complications
(12/40 patients developed deep vein thrombosis or pulmonary embolism). A recent report of the
combination of irinotecan with bevacizumab (an anti-vascular endothelial growth factor monoclonal
antibody) revealed a very high ORR of 63% among 32 patients with recurrent high-grade astrocytoma
(predominantly GBM) in whom initial radiation and concurrent temozolomide had failed.298
Treatment was well tolerated and resulted in a PFS-6 of 38%. This combination is promising, but
requires further evaluation.
This patient group is ideal for consideration of participation in clinical trials of new agents. (See
Chapter 3 Clinical trials.)
Recommendation
Level
References
Chemotherapy has modest activity in recurrent high-grade
astrocytoma. A decision on its use should be made after
discussion of risks and benefits, and consideration of other
therapeutic options, but is generally recommended for good
performance patients.
III
290–292
Optimum duration of temozolomide treatment in patients with recurrent high-grade astrocytoma
A literature review found 16 trials examining the use of temozolomide in recurrent GBM, and 14 for
AA, none of which were relevant to the question. There is no evidence to guide clinicians as to how
High-grade astrocytomas
113
long to treat patients with recurrent disease with temozolomide, and the decision should be
individualised, with emphasis on symptoms, comorbidities, toxicity of treatment, imaging, and patient
preference.
Key point:
•
The optimal duration of temozolomide treatment in patients with recurrent high-grade
astrocytoma is not yet defined.
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9
OLIGODENDROGLIOMAS
9.1
Introduction
In recent years the histological criteria for oligodendrogliomas have been better defined. The rate of
diagnosis is increasing and may now make up to 25% of newly diagnosed malignant glioma.1 This
may be because of the improved prognosis, and response to therapy, particularly chemotherapy. The
incidence appears to be similar across races.2 Oligodendroglioma grade II tumours commonly present
in the late 30s and early 40s2,3, and anaplastic oligodendroglioma (grade III) tumours present a decade
later and have a male preponderance of 1.5–2:1. The most common presenting symptom is partial
seizure (up to 70%). Fifty to sixty percent of tumours are located in the frontal lobe although they may
occur anywhere within the white matter.4 However, the diagnosis of oligodendroglioma has also
shown the limitations of pathology, and has been one of the early pointers to the importance of
biological markers in directing therapy.
9.2
Problems with diagnosis
The definition of oligodendroglial tumours is fraught with difficulty. �Pure’ oligodendrogliomas (OG)
have a classic appearance, but as they become more aggressive they dedifferentiate and become less
typical. Mixed oligoastrocytoma (OA) is even more difficult to precisely delineate.
9.2.1
Radiologic appearance
Oligodendroglial tumours, particularly those of lower grade, tend to involve the cerebral cortex and
subcortical white matter. Classically, they have been characterised by calcification.
More recently, there have been a number of imaging signatures comparing tumours that have
deletions of 1p and 19q (1p-/19q-) to those oligodendroglial tumours without such losses. In
summary, 1p-/19q- tumours are characterised by frontal lobe involvement (compared to temporal lobe
in tumours with intact alleles), more commonly cross the midline, an indistinct border (versus a
sharply defined edge), the presence of calcification or its MRI equivalent of paramagnetic changes.5
As well, imaging with Thallium SPECT and FDG PET may show increased activity above that
expected for a low grade glioma in oligodendroglial tumours with 1p/19q allelic loss.6,7 Cerebral
blood volume (CBV) maps have been used to assess the grade of glioma by measuring vascular
density. There is generally a good correlation with grade except for low-grade oligodendrogliomas in
which the CBV is also increased. This may be explained by the known �chicken wire’ vascular pattern
characteristic of classic oligodendroglial tumours.8
9.2.2
Pathologic criteria
The pathological diagnosis of an oligodendroglial tumour remains subjective, and there is
considerable inter-observer variability (see Chapter 6 Diagnosis and pathology). Diagnosis is most
difficult for oligoastrocytomas for which consensus is difficult to achieve even amongst experienced
neuropathologists.
9.2.3
Biologic markers
Refer to Chapter 6 Diagnosis and pathology
Role of 1p/19q deletions and other genetic abnormalities in management decisions
Combined 1p and 19q deletions (1p-/19q-) from tumour chromosomes have been identified as an
important predictor of improved prognosis in patients with oligodendroglial tumours (see discussion
below and in Chapter 6 Diagnosis and pathology) and should be performed in all tumours with
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oligodendroglial features. 1p-/19q- predicts for a significant response to therapy, whether that will be
radiotherapy or chemotherapy. The mechanism of this action is not understood.
Key point:
•
1p/19q testing should be performed on all tumours with oligodendroglial features.
Techniques used to assess: FISH versus LOH
Refer to Chapter 6 Diagnosis and pathology for further information.
9.3
Management
It is recognised that current optimal treatment modalities for OG and OA are unlikely to be curative
and that there is a wide variation in the overall prognosis depending on the underlying pathology
(grade II better than grade III, favourable cytogenetic aberrations), which may influence outcome
irrespective of treatment types and the order in which they are administered.
9.3.1 Low-grade oligodendroglioma
In young patients who present with seizures, or who have an asymptomatic tumour found on
incidental imaging, it may be possible to delay surgery for a period of time. However, care must be
taken as it is well recognised that grade III tumours may present as non-enhancing tumours,
particularly in patients older than 40.9 Thus all patients should undergo a biopsy at presentation.
Surgery
Gross total resection of tumour has been associated with improved survival in most retrospective
studies of low-grade gliomas10,11,12, however the technical feasibility of gross total resection is limited
by the proximity of tumour to eloquent brain and the extent of tumour infiltration. The classic
definition of gross total resection in most studies is defined as the absence of residual enhancement on
contrast-enhanced post-operative MRI scan and this in itself poses problems as up to 90% of grade II
pure OG may not show initial enhancement.2 In a recent study, inability to completely resect the
tumour was related to diffuse tumour margin on T2-weighted MR images, oligodendroglioma or
oligoastrocytoma histopathologic type, and large tumour volume.11
There are some consistent radiological findings with approximately 50% of OG demonstrating
calcification, and over 80% of grade III OG and OA demonstrating post-contrast enhancement.
Histological confirmation must still be obtained to accurately classify all tumours prior to treatment13
and to permit molecular analysis.14
Recommendations
Level
References
All patients with suspected oligodendroglioma (OG) or
oligoastrocytoma (OA) should undergo a biopsy for histological
confirmation of tumour type and grade and to permit molecular
analysis.
III
13,14
Maximal gross surgical resection is recommended where
technically feasible, as this has been shown to increase survival.
IV
10,11
All suspected OGs or OAs must undergo histological confirmation
as radiological features alone are inadequate for diagnosis and
staging.
IV
9,13
Oligodendrogliomas
135
Observation
Following surgery in pathologically confirmed low-grade tumours, observation (wait and see) is an
acceptable approach in patients who do not have significant symptoms from the tumour, most
commonly patients who present with seizures. This is based on the EORTC study comparing initial
radiotherapy at diagnosis to delayed therapy at progression. The study showed that there was no
difference in overall survival between the two groups, although not surprisingly progression-free
survival was shorter in those in which treatment was delayed.15 In most patients with oligodendroglial
tumours there is a slow growth over time that averages an increase in tumour diameter of 4mm per
year prior to anaplastic transformation that may not be readily obvious when comparing successive
scans, but is more obvious when going back to an earlier scan.16 Thus observation is an acceptable
strategy for patients with gross technical resection and otherwise good prognostic factors of young
age (<40 years), low tumour grade17 and favourable cytogenetic aberrations (1p- / 19q-) which have
been consistently associated with longer survival times,14 thus allowing these patients to avoid the risk
of long-term radiotherapy toxicities until disease progression.
Recommendation
Level
References
Observation only may be an acceptable strategy in grade II
tumours with good prognostic features.
V
18
Radiotherapy
External beam radiotherapy has been used in the management of high- and low-grade gliomas in
studies that have included both astrocytic and oligodendroglial tumours types. Unfortunately its
efficacy has never been proven in a phase III study where accrual has been restricted to
oligodendroglial tumours alone. There have been two prospective, randomised studies that have
evaluated the effect of radiotherapy dose in low-grade glioma (LGG).
The NCCTG/RTOG/ECOG study randomised 203 adult patients with LGG, post-resection/biopsy, to
50.4Gy in 28 fractions over 5.5 weeks or 64.8Gy in 36 fractions over seven weeks.19 On central
review 70% of patients participating in this study had oligodendrogliomas or mixed tumours. At five
years, there was no statistically significant difference in overall survival between the low-dose and
high-dose treatment arms; 72% versus 64% respectively.
Similarly, a study conducted by the EORTC assigned 379 adult patients with pathologically
confirmed LGG to either 45Gy in 25 fractions or 59.4Gy in 33 fractions. Not subjected to central
pathology review, only 31% were reported as oligodendrogliomas or mixed tumours.
There was no significant difference in five-year progression-free (47% and 50%) or overall survival
(58 versus 59%) between the low-dose and high-dose arms.20 The optimal timing of radiotherapy in
the treatment of LGG is controversial.
Recommendations
Level
References
External beam radiotherapy is a standard treatment for lowgrade OG and OA.
II
19,20
The recommended radiotherapy dose for low-grade OG and OA
is 50Gy in 2Gy fractions over six weeks.
II
19
An EORTC study (22845) performed a randomised phase III study comparing immediate postoperative radiotherapy to deferred radiotherapy upon progression in a population of adult patients
with LGG. Both groups received 54Gy in fractions of 1.8Gy over six weeks. Pathology was centrally
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
reviewed in 81%. The majority of these patients had the diagnosis of a LGG confirmed but 26% were
diagnosed with a high-grade tumour. The distribution of these patients between the treatment groups
was balanced and a subgroup analysis which excluded these patients confirmed the findings of the
intention-to-treat analysis.21
With a median follow-up of 7.8 years, immediate treatment was associated with an increase in
progression-free survival (median 5.3 years versus 3.4 years) but not overall survival (7.4 years versus
7.2 years). Participation in the quality-of-life component of the study was optional and there were
insufficient data to provide any meaningful analysis or conclusions. It is not possible therefore to
ascertain whether the longer PFS observed in the treatment arm was countered by an increase in
treatment-related side effect. Early seizure control, however, was better in the immediate treatment
group.
An argument against early radiotherapy is the concern about delayed, treatment-induced
neurocognitive dysfunction.22 This is particularly pertinent in relation to the treatment of the
asymptomatic or mildly symptomatic patient who may remain clinically stable for a protracted period
without treatment. There is evidence that neurocognitive and neuroradiologic changes are associated
with whole-brain radiotherapy and fraction sizes greater than 2Gy.23–25
To date, no large prospective randomised study has addressed this issue, however several case-control
and comparative studies do not support the view that modern radiotherapeutic techniques using
limited treatment fields and fractions sizes of <2Gy contribute significantly to long-term cognitive
disability.26 The largest of these studies26 included 195 patients with LGG. This study suggested that
the most deleterious effects on cognitive function were caused by the tumour itself and that other
medical factors, especially the use of anti-epileptic drugs, are also implicated and deserve further
study.
Recommendation
Level
References
Radiotherapy fraction size should not exceed 2Gy per day for
high-dose treatments.
II
22–26
In general, immediate post-operative treatment with conventionally fractionated, limited field
external-beam radiotherapy is recommended for patients with LGG presenting with mass effect, focal
deficits or signs of raised intracranial pressure, particularly if resection of the tumour is limited.
A cumulative radiotherapy dose of 45–54Gy in fractions of 1.8–2.0Gy over five to six weeks with the
treatment volume limited to the pre-operative tumour extent plus a margin of 1–2cm is currently
accepted as standard.
It may be appropriate to defer radiotherapy until progression for the compliant, asymptomatic patient
with LGG who has undergone a complete or near-complete resection without adverse clinical
features. They should be monitored by repeated clinical and imaging review. Further discussion of the
role of radiotherapy in LGG is given in Chapter 7 Low-grade astrocytomas.
Chemotherapy
In low-grade gliomas, it is not clear that chemotherapy adds any benefit. Chemotherapy and
radiotherapy have not been directly compared for efficacy and safety.
Chemotherapy as primary adjuvant therapy post-surgery has been tested in a number of phase II
studies, the largest of which was recently published.17 One hundred and forty nine (149) patients with
progressive low-grade gliomas were treated using standard temozolomide, correlating response to the
presence or absence of 1p- /19q-. Fifty-three percent of patients achieved a response (partial response
Oligodendrogliomas
137
= 15%; minor response = 38%), 37% had stable disease and 10% progressive disease. The median
time to maximum tumour response was 12 months (range 3–30 months). The median progression-free
survival (PFS) was 28 months. In 86 patients, tissue was available for tissue typing. In those with the
classic 1p-/19q- deletions the response rate was significantly higher, and the response to
chemotherapy was longer. Progression-free survival and overall survival were also significantly
improved. A smaller study of 28 patients looked at response to combination procarbazine, lomustine
and vincristine (PCV) chemotherapy prior to radiotherapy and showed a 52% response rate.27
Key point:
•
Response to temozolomide chemotherapy correlates with 1p-/19q-.
9.3.2 High-grade oligodendroglioma
The issues and recommendations for surgery and radiotherapy for high-grade oligodendroglial
tumours are the same as for other high-grade gliomas and are discussed in Chapter 8 High-grade
astrocytomas.
Chemotherapy
High-grade oligodendroglial tumours are usually classified under the WHO system as grade III
tumours. Some authors have referred to grade IV oligodendroglial tumours suggesting that they have
a worse prognosis.
The chemosensitivity of oligodendrogliomas was first described in the high-grade group.28 This led to
use of chemotherapy in high-grade oligodendrogliomas and later in mixed gliomas. A larger
prospective phase II study showed response rates of 75% of anaplastic �pure’ oligodendrogliomas.29
Kim reported 32 patients with mixed high-grade tumours30 and seven high-grade oligodendrogliomas.
They were treated with pre-radiation (19 patients) or post-radiation (12 patients) chemotherapy and
91% responded to the combined therapy. Median time to progression was 134 months (OA grade III),
12 months (OA grade IV) and 63.4 months (OG Grade III).30
Two randomised studies have been performed looking at the role of adjuvant PCV therapy and
relating it to1p-/19q-. EORTC 26951 compared radiotherapy (RT) following surgery to RT followed
by standard-dose PCV in 368 patients. They were required to have 25% or more oligodendroglial
component on histology.31 The median progression-free survival was significantly improved in those
receiving chemotherapy initially (23 versus 13 months; p=0.0018) while overall survival was not
significantly improved (40 versus 31 months; p=0.23). The five-year survival was 74% (RT and
PCV), 75% (RT) for those patients with 1p-/19q- versus 33% (RT/PCV) and 28% (RT) with those
without the 1p-/19q-. Clearly those with the 1p-/19q- have a different biology and better prognosis.
In the RTOG 9402 study, 289 patients were randomised to four cycles of intensive PCV before
radiotherapy of 59Gy. 1p-/19q- was detected in 46% of assessable patients, and these patients also had
a much longer survival regardless of randomised therapy. With the intensive PCV regime there was
significant chemotherapy-related toxicity, however no cases of myelodysplasia or leukaemia were
described. The five-year survival was 72% (PCV/RT) and 66% (RT) for tumours with 1p-/19q- versus
37% (PCV/RT) and 31% (RT) for those without the deletion.1
Recommendation
Level
References
Adjuvant PCV chemotherapy is not recommended for highgrade OG and OA as standard therapy because there is no
improvement in overall survival.
II
1, 31
138
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Oligodendroglial tumours with 1p-/19q- have a different biology to the other oligodendroglial
tumours, and should be studied as a separate group. Sequential therapies, radiotherapy with
subsequent PCV, initial PCV with subsequent radiotherapy with delayed chemotherapy are likely to
be equally efficacious. As well, these studied have shown the limitations of the PCV, with side-effects
related to progressive myelosupression and neuropathy due to vincristine.
A planned EORTC study will look at grade III gliomas stratified for 1p-/19q- using temozolomide in
combination with RT in different arrangements to test whether the application of the Stupp protocol
that is now standard in grade IV astrocytomas improves survival in oligodendroglial tumours without
an increase in neurotoxicity.32
Carboplatin has also been shown to have activity in recurrent oligodendroglial tumours33 although
their dosing was fixed schedule rather than with Area Under the Curve Dosing (AUC) in patients with
prior PCV therapy. Another study has shown favourable response rates with median time to
progression of eight months.34
There is evidence that temozolomide can be effective in patients who recur following prior
radiotherapy35, and to a lesser extent in patients who have had prior PCV.
Twenty patients with recurrent aggressive oligodendroglioma post-radiotherapy who then responded
to induction chemotherapy received myeloablative therapy with high-dose thiotepa and autologous
stem cell grafts. The results were disappointing and associated with three toxic deaths with an
encephalopathy related to the thiotepa.36 More recently, the same treatment was used in newly
diagnosed high-grade oligodendrogliomas.37 The authors treated 39 patients (out of 69 in total) who
completed three or four cycles of intensive PCV therapy, followed by high-dose myeloablative
thiotepa with stem cell rescue. They showed that in this young population with a median age of 43,
and good performance status, median progression-free survival was 78 months, and those who
remained disease-free had an excellent level of function, although no formal neuropsychological
testing was performed. The 1p/19q status was not formally assessed. It does suggest that such
aggressive therapy is better tolerated in newly diagnosed radiotherapy-naive patients.
A recent survey of management of anaplastic oligodendrogliomas reported responses from 20% of
members of the Society for Neuro-oncology. It suggested that there was a wide variation in the
treatment of these tumours. 1p-/19q- was associated with a reduction in the number of patients
receiving radiotherapy. Chemotherapy options included PCV and temozolomide most commonly, and
concurrent chemoradiotherapy was the most commonly applied.38
Oligodendrogliomas
139
Table 9.1
Chemotherapy regimens for high-grade oligodendroglioma
Drug/s
Dosing
Pros
Cons
Level of
evidence
Refs
Temozolomide
standard dosing
200 mg/m2 for 5
days every 28
days
Well tolerated and
active
No cumulative toxicity
Can respond second
time
Minimal
II
35
Temozolomide
alternative
scheduling
low-dose
continuous
one week on/one
week off
May be useful in
resistant tumours
Increased fatigue
Increased
lymphopaenia
IV
39
PCV
Procarbazine 60
mg/m2
Lomustine
(CCNU) 110
mg/m2
Vincristine 2
mg/m2
Prior standard
Cumulative
marrow toxicity
limiting therapy
Neuropathy & pain
Monoamine
oxidase inhibitor
(MAOI) effects
II
29,30
Carboplatin
Area under the
curve (AUC) 5–7
Good tolerability
Thrombocytopenia
No cumulative toxicity
Prolonged responses
possible
III
33,34
9.4
Follow-up of oligodendroglial tumours
(See also Chapter 14 Follow-up)
There are no data identifying the ideal follow-up frequency for patients with oligodendroglial
tumours. The principles are to closely monitor the patient initially to assess the tumour’s pattern of
behaviour, and then the interval of radiologic monitoring can be extended.
With high-grade oligodendroglial tumours imaging would be initially every three months and
gradually prolonged. With low-grade gliomas, this interval can be lengthened and even extended after
a period of observation to one-yearly intervals. Seizure management may also determine clinical
frequency.
Imaging type for follow-up
MRI is the modality of choice given the higher degree of detail it makes available. For those in whom
it is not possible (eg pacemaker or claustrophobia) CT scan is generally inferior.
9.5
Treatment of recurrence
While many of the principles relating to recurrent gliomas also apply to oligodendrogliomas, there are
specific data to guide us.
In chemo-naive patients who have recurred following radiotherapy, there is evidence that both
temozolomide and PCV are effective. Fifty-two patients who recurred following radiotherapy had a
response rate to six cycles of PCV of 63% with a median time to progression for the whole group as
ten months.40 A more recent study of 38 patients treated with a planned twelve months of
temozolomide at recurrence reported response in 20 patients. Median time to progression was 10
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
months for the group and 13 months for the responders. The drug was well-tolerated.35 A larger study
investigated 67 patients (39 patients had AP; 28 had AOA). The overall response rate was 46%. 1p/19q- was detected in half of the patients and these patients had a significantly higher response rate,
time to progression and overall survival.41 In addition, there is also evidence in patients who have
received prior chemotherapy that they can respond either to the same regimen in the case of
temozolomide, or to an alternative regime such as PCV, temozolomide or carboplatin.42–44
As a significant proportion of these patients have relatively long survivals, re-irradiation becomes a
possibility and should be discussed with a review of the prior radiotherapy regime including dose and
treatment volume.45 These options are discussed further in Chapter 8 High-grade astrocytomas.
The EORTC study reported five-year survival figures of 74% in patients with grade III
oligodendroglial tumours with 1p-/19q- status, versus 34% in those without deletions in the group
treated with radiotherapy and chemotherapy. The five-year PFS was 70% in the former, and 27% in
the latter. Similar results were reported in the RTOG study.
Low-grade oligodendroglial tumours have median overall survival of nine years (1p+/19q+) and 13
years (1p-/19q-) respectively.46
Key point:
•
Chemotherapy-naive patients with high-grade oligodendroglioma who have recurred
following radiotherapy will often respond to chemotherapy.
•
For recurrent high-grade OG, there may be a role for further chemotherapy and
consideration of re-irradiation in patients with good performance status.
References
1
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Jaeckle KA, Ballman KV, Rao RD, Jenkins RB, Buckner JC. Current strategies in treatment
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Shaw EG, Tatter SB, Lesser GJ, Ellis TL, Stanton CA, Stieber VW. Current controversies in
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Megyesi JF, Kachur E, Lee DH, Zlatescu MC, Betensky RA, Forsyth PA et al. Imaging
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6
Derlon JM, Cabal P, Blaizot X, Borha A, Chapon F. [Metabolic imaging for supratentorial
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Walker C, du Plessis DG, Fildes D, Haylock B, Husband D, Jenkinson MD et al. Correlation
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8
Lev MH, Ozsunar Y, Henson JW, Rasheed AA, Barest GD, Harsh GR et al. Glial tumor
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Barker FG, Chang SM, Huhn SL, Davis RL, Gutin PH, McDermott MW et al. Age and the
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Keles GE, Lamborn KR, Berger MS. Low-grade hemispheric gliomas in adults: a critical
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Talos IF, Zou KH, Ohno-Machado L, Bhagwat JG, Kikinis R, Black PM et al. Supratentorial
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Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S et al. Role of extent of
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Lebrun C, Fontaine D, Ramaioli A, Vandenbos F, Chanalet S, Lonjon M et al. Long-term
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Nutt CL. Molecular genetics of oligodendrogliomas: a model for improved clinical
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van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K et al. Longterm efficacy of early versus delayed radiotherapy for low-grade astrocytoma and
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Mandonnet E, Delattre JY, Tanguy ML, Swanson KR, Carpentier AF, Duffau H et al.
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Kaloshi G, Benouaich-Amiel A, Diakite F, Taillibert S, Lejeune J, Laigle-Donadey F et al.
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van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K et al. Longterm efficacy of early versus delayed radiotherapy for low-grade astrocytoma and
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Shaw E, Arusell R, Scheithauer B, O'Fallon J, O'Neill B, Dinapoli R et al. Prospective
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Karim AB, Maat B, Hatlevoll R, Menten J, Rutten EH, Thomas DG et al. A randomized trial
on dose-response in radiation therapy of low-grade cerebral glioma: European Organization
for Research and Treatment of Cancer (EORTC) Study 22844. International Journal of
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Laack NN, Brown PD. Cognitive sequelae of brain radiation in adults. Semin Oncol 2004;
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Postma TJ, Klein M, Verstappen CC, Bromberg JE, Swennen M, Langendijk JA et al.
Radiotherapy-induced cerebral abnormalities in patients with low-grade glioma. Neurology
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Taphoorn MJ, Klein M. Cognitive deficits in adult patients with brain tumours. Lancet Neurol
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Klein M, Heimans JJ, Aaronson NK, van der Ploeg HM, Grit J, Muller M et al. Effect of
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in low-grade gliomas: a comparative study. Lancet 360(9343):1361–8, 2002.
27
Buckner JC, Gesme D, Jr., O'Fallon JR, Hammack JE, Stafford S, Brown PD et al. Phase II
trial of procarbazine, lomustine, and vincristine as initial therapy for patients with low-grade
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abnormalities. J Clin Oncol 2003; 21(2):251–255.
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anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J
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lomustine, and vincristine (PCV) chemotherapy for grade III and grade IV oligoastrocytomas.
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Brandes AA, Tosoni A, Cavallo G, Reni M, Franceschi E, Bonaldi L et al. Correlations
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906.
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10
10.1
COMPLEMENTARY, ALTERNATIVE AND UNPROVEN
THERAPY
Introduction
Despite the significant improvement in conventional medical treatments, the outlook for many people
with malignant glioma remains poor. It is not, therefore, surprising that an increasing number of
patients and their carers will seek other therapeutic options.1,2 These treatments are often referred to as
�complementary and alternative medicines’ or �CAM’. In combination with conventional approaches
they are sometimes known as �integrative medicine’.
Integrative medicine has been defined as �conventional medicine working together with nutrition,
supplements, exercise, and mind–spirit care, incorporating the insights and practices of
complementary medicine, traditional non-Western medicine, and alternative medicine, when
appropriate, directly with conventional approaches’.3
�Complementary’ implies synergy with mainstream medicine either to improve the therapeutic
outcome or to affect quality of life by ameliorating side-effects of treatment.
�Alternative’ medicine includes therapies that are promoted as a substitute for conventional cancer
treatments.
There is no unifying definition of CAM but the types of intervention may include:
•
systemically administered treatments (plant and animal extracts, dietary modifications, vitamins,
hormonal treatments, pharmaceuticals not usually used in cancer treatment, immune modulating
substances)
•
acupuncture
•
massage and touch therapies
•
psychological therapy including counselling, group therapy, relaxation, hypnosis, meditation and
spiritual healing
•
homeopathy
•
non-invasive medical devices or procedures (eg delivery of low-intensity alternating electrical
fields to the brain)
The prevalence and popularity of CAM use in the general population has been well documented in
recent years, with rates of use ranging from 25% to 69% in Australia, UK, mainland Europe and
USA.4–6 At one comprehensive cancer centre in the USA over 80% of patients reported using CAM..7
A study looking specifically at CAM use and quality of life in patients with primary brain tumours8
found that 34% of patients reported using CAM and 74% of these stated that their physician was
unaware. Higher performance status was the only factor significantly related to CAM usage. In the
general cancer population other factors influencing increasing use include age (younger), sex (female)
and pay status (higher).7
There are potential benefits as well as possible problems associated with the use of CAM in the
treatment of brain tumours (as well as other malignant and non-malignant medical conditions).
Complementary, alternative and unproven therapy
145
10.2
Potential benefits
A major motivation of the interest in CAM is the perceived or real failure of mainstream medicine to
provide desired outcomes. CAM offers the hope of access to more effective treatment with the
implied promise of extended survival and improved symptom control.
Other potential benefits include:
•
Improved sense of psychological control: initiating a strategy that is independent of the medical
•
Improved side-effect profile: complementary strategies may ameliorate symptoms associated with
•
Access to less toxic treatment: CAM is regarded as �natural’ and thus is assumed to have less
•
The placebo effect: �placebo’ is Latin for �I will please’ and refers to any medical treatment that is
inert, that is, has no action. Numerous clinical trials have reported clinical benefits in subjects on
the placebo treatment. Some CAM treatments such as homeopathy, faith healing and meditation
may provide benefit through the placebo effect.
•
Restoration of hope in the face of an often dismal prognosis.
model gives the promise of exerting greater control over the disease process and the treatment
itself.
conventional treatments such as chemotherapy and radiotherapy.
toxicity.
In one recent study7 that examined CAM usage in cancer patients, the most common reason reported
for CAM use was a desire to feel hopeful (73%). Other reasons cited were belief that these treatments
were less toxic and the desire to have more control over the decisions about medical care.
10.3
Possible problems
There are a number of real potential problems:
•
The toxicity of many �natural’ remedies is either unknown or not readily available. There have
been numerous reports of unexpected side-effects associated with CAM use in various cancers,
for example, doses of selenium >1000mcg/day may cause muscle weakness, fatigue, peripheral
neuropathy, dermatitis and liver damage.
•
Potential interactions with conventional drugs are often not recognised or reported. One study
estimated that of patients taking chemotherapeutic drugs and CAM, at least 27% were at risk of
developing CAM–chemotherapy drug interactions.9 The herbal product St John’s Wort (SJW) is
popular because of proposed anti-depressant activity. However, through the mechanism of hepatic
enzyme induction, SJW has been shown to decrease the plasma levels of both irinotecan and
imatinib (chemotherapy agents) in a clinically significant manner.10
•
Purity of herbal remedies and dietary supplements can be problematic since in general the
manufacturing quality and labelling are not as strictly controlled as pharmaceutical drugs.
Contaminants and/or unrecognised ingredients have the potential to cause drug interactions and
direct toxicity.11
•
Many of the marketed CAM are expensive, adding an additional burden to an already stressful
environment. Twenty percent of patients in one study admitted to spending more than US$100 per
month on CAM.8
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
•
The issue of �false hope’ may be important. Approximately one third of patients in one survey7
expected CAM therapies to cure their disease. There is no real evidence outside of anecdotal
reports that cure is a realistic goal.
10.4
Discussion
There are a number of interventions that may fall within the CAM definition that have shown
promise, have demonstrated benefit or are part of mainstream management of cancer patients.
The definition of clinical benefit includes psychological and physical symptom control (quality of life
[QOL]) as well as direct anti-tumour effects. It is important to distinguish between QOL effect and
tumour control.
Generally �alternative’ treatments have been disappointing in terms of anti-tumour activity whereas
�complementary’ treatments have good evidence to support activity in symptom control and QOL
improvement.
The following are interventions with principally QOL benefit:
10.4.1
Counselling, support and psychological treatments
A range of psychological interventions are commonly used in cancer care (including brain tumours)
and are part of mainstream management. There is high-level evidence from meta-analyses supporting
this approach to improve well-being, although it does not affect survival.12–14 However, lack of access
to appropriately trained neuropsychologists and counsellors is a significant problem reported by brain
tumour patients and their families.
10.4.2
Meditation and relaxation
The aims of meditation are to achieve relaxation and/or more spiritual goals. There are also specific
relaxation techniques that do not involve meditation. There is clinical trial evidence that some form of
relaxation reduces stress and pain and improves QOL of cancer patients.15,16
10.4.3
Acupuncture
Acupuncture is a method developed by traditional Chinese medicine using stimulation of acupuncture
points on the body by needle, pressure, electric current or laser. There have been numerous clinical
trials with conflicting results but there is evidence that acupuncture is useful in the treatment of
nausea and vomiting (including chemotherapy induced) as well as pain.17 This has been confirmed by
a recent Cochrane review which identified acupressure as reducing the likelihood of nausea the day
after chemotherapy (but not on subsequent days) and electro-acupuncture as reducing first-day
vomiting.18
10.4.4
Massage and touch therapies
There is some evidence that massage therapy is helpful in the management of cancer pain. A recent
randomised trial examining the benefit of aromatherapy massage in the management of anxiety and
depression in patients with cancer reported no improvement in symptoms at ten weeks but a
significant benefit at six weeks.19 However, another randomised study of radiotherapy patients found
that anxiety scores were significantly worse in aromatherapy patients.20
10.5
Systematically administered therapies
Some of the herbal and related compounds have been shown to reduce cancer- or treatment-related
symptoms, for example, ginger and cannabis for nausea and vomiting, valerian for insomnia.21
Referring specifically to anti-tumour activity of CAM, the following points can be made:
Complementary, alternative and unproven therapy
147
•
A systematic review of clinical trials of unconventional anti-cancer agents concluded that these
treatments had not been the subject of appropriate early-phase trial development.22 This fact
together with the assertion that many CAM (such as homeopathy) are not suited to analysis by
conventional clinical trial design means that there is a paucity of evidence to support their
antineoplastic activity.
•
In relation to malignant glioma, there is no high-level evidence that any complementary,
alternative or unproven medicines have any significant antineoplastic activity
10.5.1
Homeopathy
This is based on the similarity theory, where the patient’s symptoms are matched to side-effects of a
known substance with the idea that �like cures like’. The substance is diluted to a very low
concentration (even to a level where only a single molecule may be present) prior to administration
and attention is also given to aspects of lifestyle. Proponents of this treatment contend that by its
nature it is not suitable for evaluation by traditional scientific instruments.
However a meta-analysis of all randomised placebo-controlled trials concluded that the clinical
benefits were not entirely placebo effect.23 There was no evidence of benefit for stroke or headache.
Other neurological or oncological conditions were not examined.
The dilute nature of the treatment probably means that the risk of toxicity is very low.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points:
•
There is no unifying definition of CAM and treatment that may fall within the definition of
�complementary’, such as counselling, has high-level evidence to support its use.
•
There is evidence for an increasing interest in and use of CAM.
•
Antineoplastic activity of CAM in malignant glioma is supported by low-level evidence,
such as case reports, and cannot be recommended.
•
There needs to be a distinction between quality-of-life benefits and antineoplastic
activity when assessing potential benefit.
•
Quality of life and /or symptom management such as control of nausea and vomiting
with acupuncture are supported by good evidence.
•
Some of the modalities that may fall within the definition of CAM (eg counselling) are
part of mainstream clinical practice and supported by high-level evidence.
•
There are potentially very important toxicities associated with CAM caused by
interactions with conventional medicines and primary toxicity.
•
Many patients do not discuss CAM usage with their medical practitioner.
•
For malignant glioma there is no high-level evidence for antineoplastic activity of CAM.
•
Clinicians should inquire about the use of CAM in a non-confronting and nonjudgemental way.
•
Health professionals should not participate in the administration of unproven treatments.
10.5
Summary
There is little doubt that CAM will remain an integral and often unrecognised part of treatment
strategies employed by patients with malignant glioma. In view of the potential toxicity and the
frequent non-disclosure associated with CAM it is most important that treating physicians make direct
and non-judgemental enquiry of their patients about CAM usage.
It is important that patients are thus able to obtain the best advice about the possible problems of
toxicity and cost of CAM versus the potential benefits in terms of quality of life, symptom control and
putative antineoplastic activity.
It is preferable to discuss all of these treatments in an atmosphere of collaboration rather than risk
covert use of damaging substances or devices.
Comprehensive information about the safety and efficacy of CAM as well as clinical trials is available
from several reputable web sites including:
• The Cancer Council Australia (<www.cancercouncil.org.au>)
• The M. D. Anderson Cancer Centre (<www.mdanderson.org/departments/CIMER/>)
• Memorial Sloan-Kettering Cancer Centre (<www.mskcc.org>)
• National Institute of Health (<nccam.nih.gov/>)
Complementary, alternative and unproven therapy
149
References
1
Molassiotis A, Fernadez-Ortega P, Pud D, Ozden G, Scott JA, Panteli V et al. Use of
complementary and alternative medicine in cancer patients: a European survey. Annals of
Oncology 16(4):655–63, 2005.
2
Yates JS, Mustian KM, Morrow GR, Gillies LJ, Padmanaban D, Atkins JN et al. Prevalence
of complementary and alternative medicine use in cancer patients during treatment.
Supportive Care in Cancer 13(10):806–11, 2005.
3
Block KI, Jonas WB. "Top of the hierarchy" evidence for integrative medicine: what are the
best strategies? Integrative Cancer Therapies 5(4):277–81, 2006.
4
Fisher P, Ward A. Complementary medicine in Europe. BMJ 309(6947):107–11, 1994.
5
MacLennan AH, Wilson DH, Taylor AW. Prevalence and cost of alternative medicine in
Australia. Lancet 1996; 347(9001):569–573.
6
Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M et al. Trends in
alternative medicine use in the United States, 1990–1997: results of a follow-up national
survey. JAMA 1998; 280(18):1569–1575.
7
Richardson MA, Sanders T, Palmer JL, Greisinger A, Singletary SE.
Complementary/alternative medicine use in a comprehensive cancer center and the
implications for oncology. J Clin Oncol 2000; 18(13):2505–2514.
8
Armstrong T, Cohen MZ, Hess KR, Manning R, Lee EL, Tamayo G et al. Complementary
and alternative medicine use and quality of life in patients with primary brain tumors. Journal
of Pain & Symptom Management 32(2):148–54, 2006.
9
McCune JS, Hatfield AJ, Blackburn AA, Leith PO, Livingston RB, Ellis GK. Potential of
chemotherapy–herb interactions in adult cancer patients. Supportive Care in Cancer
12(6):454–62, 2004.
10
Meijerman I, Beijnen JH, Schellens JH. Herb–drug interactions in oncology: focus on
mechanisms of induction. Oncologist 11(7):742–52, 2006;-Aug.
11
Ernst E. Adverse effects of herbal drugs in dermatology. British Journal of Dermatology
143(5):923–9, 2000.
12
Devine EC, Westlake SK. The effects of psychoeducational care provided to adults with
cancer: meta-analysis of 116 studies. Oncol Nurs Forum 1995; 22(9):1369–1381.
13
Meyer TJ, Mark MM. Effects of psychosocial interventions with adult cancer patients: a
meta-analysis of randomized experiments. Health Psychol 1995; 14(2):101–108.
14
Sheard T, Maguire P. The effect of psychological interventions on anxiety and depression in
oncology: results of two meta-analyses. Psychooncology 2001; 5(3 (S)):19.
15
Ernst E. Complementary therapies in palliative cancer care. Cancer 2001; 91(11):2181–2185.
16
Vickers AJ, Cassileth BR. Unconventional therapies for cancer and cancer-related symptoms.
Lancet Oncol 2001; 2(4):226–232.
17
NIH Consensus Development Panel on Acupuncture. Acupuncture. JAMA: The Journal of
the American Medical Association 1998; 280(17):1518–1524.
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18
Ezzo JM, Richardson MA, Vickers A, Allen C, Dibble SL, Issell BF et al. Acupuncture-point
stimulation for chemotherapy-induced nausea or vomiting. Cochrane Database of Systematic
Reviews (2):CD002285, 2006.
19
Wilkinson SM, Love SB, Westcombe AM, Gambles MA, Burgess CC, Cargill A et al.
Effectiveness of aromatherapy massage in the management of anxiety and depression in
patients with cancer: a multicenter randomized controlled trial. Journal of Clinical Oncology
25(5):532–9, 2007.
20
Graham PH, Browne L, Cox H, Graham J. Inhalation aromatherapy during radiotherapy:
results of a placebo-controlled double-blind randomized trial. J Clin Oncol 2003;
21(12):2372–2376.
21
Hall W, Christie M, Currow D. Cannabinoids and cancer: causation, remediation, and
palliation. Lancet Oncol 2005; 6(1):35–42.
22
Vickers AJ, Kuo J, Cassileth BR. Unconventional anticancer agents: a systematic review of
clinical trials. Journal of Clinical Oncology 24(1):136–40, 2006.
23
Mathie RT. The research evidence base for homeopathy: a fresh assessment of the literature.
Homeopathy 2003; 92(2):84–91.
Complementary, alternative and unproven therapy
151
11
SYMPTOM MANAGEMENT AND COMPLICATIONS
Patients with gliomas may suffer from a number of medical problems as a result of the primary
disease or its treatments. Patients are frequently on multiple medications and clinicians should be
aware of the risks of drug to drug and drug to complementary medicine interactions. Some of the
treatment-related complications are dealt with in the chapters covering those treatments. Other
common medical issues–seizure control, the use and complications of corticosteroids, skin reactions
and thromboembolic events–are covered in this chapter.
11.1
Seizures
11.1.1
Seizure incidence and management
Most patients with tumour-related epilepsy have seizure as their presenting symptom. The incidence
of seizures prior to diagnosis is 10–40%.1,2 The incidence varies depending on the age of patient, and
histology and site of tumour3 with younger age and lower-grade tumours tending to be more likely to
present with seizures.4
Seizures may be the only or principal source of disability. Seizures may arise as a result of the tumour
or as a consequence of surgery. When disabling epilepsy occurs as a result of a low-grade glioma,
ablative surgery is sometimes performed purely to eliminate seizures rather than for tumour control.5
Seizure types
Most seizures due to brain tumours are focal (partial) seizures. If the patient remains conscious during
the seizure, it is known as a simple partial seizure, while complex partial seizures are those where
consciousness is impaired (the patient does not respond or does not remember the content of the
seizure).6 Focal seizures may produce almost any episodic neurological symptom, from dГ©jГ vu or
olfactory hallucinations through to focal twitching or paraesthesia. A focal seizure may evolve to a
secondary generalised tonic-clonic seizure.
Prophylactic anti-epileptic drug therapy
Anti-epileptic drug (AED) therapies have been prescribed prophylactically to prevent seizures in any
patient with a glioma or in those undergoing neurosurgery. However the evidence does not support
such a strategy. A Mayo Clinic meta-analysis found only five relevant studies.7 These studies often
included all patients undergoing craniotomy (including non-tumour patients and extra-axial tumours),
or all types and sites of intracranial tumour.8,9 Studies of patients with glial tumours have included all
grades of tumour. Both these issues make the results more difficult to interpret but there was no
evidence of a benefit for prophylactic AED.
A small proportion of patients (perhaps 10%) develops seizures at the time of or within the first week
after surgery.2,10 The use of prophylactic anticonvulsants in this setting has been a controversial issue
for many years. In the 1990s, a US survey found over 80% of neurosurgeons used prophylactic preoperative anticonvulsants in patients with tumours of all types.1 Few studies have looked specifically
at the benefit of peri-operative anticonvulsants.8,9 These have shown no clear benefit in reducing the
likelihood of post-operative seizures.
Epilepsy develops later in the course of treatment in another small (approximately 10–15%)
proportion of patients.3
In summary, there is currently no evidence to support the use of prophylactic anticonvulsants in
patients with gliomas, either at presentation or at time of surgery.1,7 If a patient has already been
started on AEDs and remains seizure free, AED should be gradually withdrawn over a period of
weeks.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Recommendation
Level
References
Prophylactic anticonvulsants are not recommended. However,
once started, an anticonvulsant is best withdrawn over several
weeks.
I
1,6
11.1.2
Epilepsy management
The main steps in epilepsy management are:
Confirm diagnosis
Not all episodic neurological symptoms in patients with gliomas are seizures. The diagnosis of
seizures relies heavily on the history, including that provided by a witness to the event. EEG may
provide confirmation but gliomas can cause EEG abnormalities without seizures. False negative EEG
may also occur. If the nature of recurrent neurological episodes remains unclear, recording an episode
with video-EEG monitoring may provide the diagnosis.
Counsel
Patients and their carers should be advised about the following issues including:
First aid
Minimising risks from seizures at home (bathing, heaters), at work (heights, machinery, vehicles) and
at leisure (swimming, climbing).
When to call an ambulance
After the first seizure, for prolonged seizures (more than five minutes), second seizure before
recovery from first seizure, repeated seizures within 24 hours, failure to return to consciousness after
ten minutes, and if there has been a physical injury.
Driving
National standards for assessing fitness to drive have been published by Austroads11 and include
standards for patients with epilepsy (as well as those with brain tumours or a recent craniotomy). In
summary, patients may not drive after their first seizure unless they remain free of seizures over the
ensuing six months. After a diagnosis of epilepsy (recurrent seizures) is made and therapy started,
driving may resume if no seizures have occurred in the next six months. Continuing seizures are not
compatible with safe driving. More information on driving is given in Chapter 13 Rehabilitation.
Avoidance of seizure precipitants
Sleep deprivation, excessive alcohol, certain non-prescription and illicit drugs.
Medication issues
Avoidance of sudden withdrawal of AED, missed doses, timing, drug interactions
Prognosis
Only 60–70% of patients with focal seizures are fully controlled by AED therapy.12,13 It should be
explained to the patient that if the initial dose of the initial drug does not control seizures, there are
many therapeutic options available to try to fully suppress seizures.
Support groups can be very helpful in providing information, practical advice and psychosocial
support.
Symptom management and complications
153
Decide whether to treat
A single seizure
The risk of further seizures in unselected patients is about 50%.14 However this risk is increased in the
presence of structural brain lesions, including gliomas and in patients with epileptiform abnormalities
on EEG. Treatment after the first seizure has been shown to reduce the risk of subsequent seizures
during therapy.15,16 However, this benefit has to be weighed against potential side effects and the
inconvenience of daily therapy. Compliance can also be a problem in situations where the need for
therapy is less obvious to the patient. The decision to treat after the first seizure or to defer it to the
next seizure may need to be individualised after discussing the advantages and risks with the patient.
Recommendation
Level
References
Anticonvulsant treatment should be commenced after the first
seizure in patients with gliomas.
II
14,15
Recurrent seizures
In this situation, it is clear that an AED should be prescribed because the risk of subsequent seizures is
very high.17,18
Choice of drug
Carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) are the standard agents in focal
epilepsy (whether seizures evolve to generalised tonic/clonic [GTC] seizures or remain focal). CBZ
and PHT are considered slightly more efficacious than VPA but the difference is small.19 PHT and
CBZ are both hepatic cytochrome p450 enzyme inducers, which may lead to accelerated metabolism
of other hepatically metabolised drugs including corticosteroids and anticoagulants. PHT has the
advantage of being available in an intravenous (IV) form but dosing must be individualised and its
first order pharmacokinetics means that small changes in dose can produce large changes in serum
level. IV PHT requires a loading dose of approximately 15mg/kg. The adequacy of the loading dose
should be checked with a serum level performed one hour later. However, this will not predict the
maintenance dose requirement. When immediate suppression of seizures is not required, an oral
loading dose can be given. PHT serum levels are well correlated with toxicity and efficacy.20. A
common error is to increase or decrease the dose in 100mg steps, which often results in an excessive
change in level, resulting in seizures or toxicity. It is preferable in most circumstances to change the
dose by one 50mg tablet or one to two 30mg capsules.
VPA may interfere with platelet function and number and many neurosurgeons prefer that it be
avoided in patients undergoing craniotomy. VPA is available in an IV form.
CBZ should be introduced over several weeks with a slow increase up to an effective dose to reduce
sedation, especially in the elderly. The newer AEDs–lamotrigine (LTG), topiramate (TPM),
gabapentin (GBP), tiagabine (TGB), oxcarbazepine (OXC), leviteracitam (LEV) and pregabalin
(PRG)–have some advantages, including a lower potential for drug interactions in most but are
available in Australia under the PBS (with the exception of PRG) only where the standard AEDs are
ineffective. They have not been demonstrated to have superior efficacy to CBZ. However, they can be
very useful when seizures are not fully suppressed by standard AEDs. They should be added to the
standard drug and then, if seizures become fully controlled, the standard drug may be tapered to
establish whether the improvement is due to the combination or the additional drug alone.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Table 11.1
Characteristics of commonly used anti-epileptic drugs
CBZ
PHT
VPA
Efficacy against focal seizures
++
++
+
Enzyme inducer
yes
yes
no
Unfavourable pharmacokinetics
no
yes
no
Usefulness of serum levels
somewhat
very
little
IV formulation
no
yes
yes
Effect on haemostasis
no
no
yes
Can be started at full dose
no
yes
no
Allergic skin reactions
yes
yes
no
AED interactions
CBZ and PHT are hepatic cytochrome P450 enzyme inducers and enhance the metabolism of many
drugs, including commonly-used agents such as corticosteroids, warfarin and oral contraceptives21,
the dose of which may need to be increased to obtain the desired effect. CBZ metabolism is inhibited
by erythromycin, clarithromycin, diltiazem and metronidazole22, which can result in CBZ toxicity.
The ability of some AEDs to stimulate the cytochrome P450 enzyme system markedly accelerates
the metabolism of many chemotherapeutic agents, including nitrosoureas, paclitaxel,
9-aminocamptothecin, thiotepa, topotecan and irinotecan, as well as the newer targeted molecular
agents such as imatinib, gefitinib, temsirolimus, erlotinib and tipifarnib. This potentially reduces the
effectiveness of these agents because the biologically active dose of these chemotherapeutic agents in
brain tumour patients taking an enzyme-inducing AED (EIAED) may be much lower than in patients
not taking EIAED.
Valproic acid has particular properties that complicate its use with specific chemotherapeutic agents.
It inhibits the glucuronidation of SN-38, the active metabolite of irinotecan, and thus triples the AUC
of SN-38 in laboratory animals. Additionally, it has been shown to inhibit histone deacetylase, a target
of several chemotherapeutic agents in development including suberoylanilide hydroxamic acid
(SAHA, Vorinostat) and depsipeptide (FK228). Its use in patients receiving these agents should
therefore be avoided.2
Many chemotherapeutic agents induce coenzymes of the cytochrome P450 pathway and change the
plasma concentration of concomitantly prescribed antiepileptic drugs. Cisplatin, vincristine, and
doxorubicin can reduce the activity of carbamazepine and phenytoin. Methotrexate can reduce the
plasma concentration of valproic acid. Doxorubicin and cisplatin can decrease the plasma
concentration of carbamazepine or valproic acid. The toxic effects of valproic acid are increased when
combined with cisplatin or nitrosureas. Combination of phenytoin with fluoropyrimidines (ie
fluorouracil, tegafur, and capecitabine) increases phenytoin’s toxic effects, and treatment failure has
been noted in combination with tegafur. New anti-epileptic drugs such as gabapentin, levetiracetam,
and pregabalin do not interact with other agents as they do not influence the cytochrome P450 or other
metabolic pathways. To date, no or few side effects have been reported with levetiracetam in several
series of patients with brain tumours who received concomitant antineoplastic agents.23
11.1.3
Monitoring treatment
Serum AED levels are most useful for PHT because of its first order pharmacokinetics.20 However,
evidence for the usefulness of levels for CBZ, VPA and the newer AEDs is lacking and clinical
Symptom management and complications
155
monitoring is preferable to pre-emptive changes in patients without symptoms or signs of toxicity or
continuing seizures.24
Cessation of AED therapy
When patients taking AEDs have had no seizures for a considerable time, there are two possible
explanations: either the epilepsy is in remission and AEDs are no longer needed or the epilepsy is still
active but suppressed by AEDs. Unfortunately, the only reliable way to discover which applies is to
withdraw therapy and observe whether seizures occur. When this strategy was applied to a group of
patients with epilepsy from various causes who had experienced two years without seizures,
approximately 50% of patients remained seizure free.25 Recurrence was more likely if there was any
underlying neurological disorder.25 The decision to withdraw or continue therapy in seizure-free
patients must be individualised and should take into account the severity of the seizures, the presence
of AED side effects, the need to continue driving (National standards require cessation of driving
during medication taper and for three months thereafter11), the patient’s views on continuing possibly
unnecessary therapy and the acceptability of experiencing further seizures. In patients with high-grade
tumours and a short life expectancy, the benefits of withdrawing therapy are usually outweighed by
the high likelihood of seizure recurrence.
Recommendation
Level
References
If a decision to discontinue anticonvulsants is made, the drug
should be withdrawn slowly, over two to three months.
I
1
Surgery for epilepsy
Surgical resection of gliomas producing seizures should be considered where AEDs are not
controlling seizures, the epilepsy is significantly impairing quality of life and the tumour can be
resected without unacceptable neurological deficit.26 The low grade of a tumour and lack of
neurological deficit should not argue against surgery and, in fact, may favour it because the benefits
of surgery will extend over a longer lifespan than in higher-grade tumours. Extensive investigation is
required to establish that the seizures are originating from the region of the tumour and to predict the
effects of resection (both favourable and unfavourable). This includes video-EEG monitoring to
capture both the clinical and EEG features of the seizures, MRI, functional MRI, ictal SPECT, interictal PET and neuropsychological assessment.
11.2
Corticosteroids
The blood–brain barrier within a brain tumour and in the blood vessels surrounding the brain tumour
is disrupted due to the loss of tight junctions between endothelial cells, increased pinocytosis in the
endothelium and an increase in endothelial fenestrations.2 Disruption of the blood–brain barrier results
in accumulation of extracellular fluid in the brain parenchyma. Oedema contributes to the morbidity
associated with a brain tumour.
The indication for treatment with corticosteroids is symptomatic cerebral oedema.27 Treatment with
corticosteroids has not been evaluated in a randomised clinical trial, but there is general agreement
that patients with clinical and radiological evidence of oedema surrounding a brain tumour should be
treated with corticosteroids. Patients undergoing radiotherapy to large volumes of brain benefit from
corticosteroids, which reduce radiation-induced cerebral oedema and relieve headache and nausea.
No randomised trial has compared different corticosteroid agents in patients with brain tumours.
Dexamethasone is generally used because it has less mineralocorticoid activity than the other
corticosteroids.2
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
The optimum dose of dexamethasone is unknown. The usual starting dose is 16mg per day divided
into two to four doses, but if necessary, the dose may be increased up to 100mg per day.2 There has
been no randomised trial comparing different doses of dexamethasone in patients with a malignant
glioma, but lower doses (4mg or 8mg/day) may be equally effective. Doses as low as 2mg/d may be
effective in preventing radiotherapy-induced cerebral oedema.
Recommendation
Level
References
Treatment with dexamethasone is recommended in patients who
are symptomatic and have cerebral oedema. The usual starting
dose is 16mg per day.
IIII
26
The risk of complications is related to the corticosteroid dose28 and the duration of treatment.
Therefore, the dose should be gradually reduced to the lowest amount that controls the patient’s
symptoms.27,29 If possible, corticosteroids should be gradually withdrawn after radiotherapy has been
completed.
Recommendation
Level
References
The dose of dexamethasone should be gradually tapered to the
lowest amount that controls the patient’s symptoms.
Dexamethasone should not be discontinued abruptly.
IIII
26,28
Dexamethasone is usually not indicated in patients with asymptomatic oedema identified on imaging.
Patients and their relatives should be provided with written guidance about the corticosteroid dose and
potential side effects.
Patients should be monitored for side effects, especially hyperglycaemia, proximal myopathy and
weight gain.
Recommendation
Level
References
Blood glucose concentrations, upper and lower limb power and
weight should be assessed prior to starting corticosteroids and at
regular intervals after treatment is started.
IIII
2
11.3
Gastrointestinal side effects
The risk of peptic ulcer disease and gastrointestinal haemorrhage is low when patients are treated with
corticosteroids alone. The risk of peptic ulcer disease increases when corticosteroids are used with a
non-steroidal anti-inflammatory drug (NSAID). Misoprostol, proton pump inhibitors and high-dose
H2-receptor antagonists are effective in preventing chronic NSAID-related endoscopic gastric and
duodenal ulcers, but only misoprostol 800 Ојg/day reduces the risk of ulcer complications such as
perforation or haemorrhage.30.Although misoprostol is the most effective agent in preventing peptic
ulcer disease and its complications, its use is often limited by side effects such as diarrhoea. Proton
pump inhibitors are usually preferred, because they are reasonably effective and they have fewer side
effects. Treatment with a proton pump inhibitor should be considered in patients who have a high risk
of peptic ulcer disease and gastrointestinal haemorrhage during treatment with corticosteroids:
patients receiving high doses of dexamethasone; patients receiving a NSAID or anticoagulant with
corticosteroid; and in patients with a past history of peptic ulcer disease.2,27
Symptom management and complications
157
Recommendation
Level
References
Treatment with a proton pump inhibitor is recommended if a
patient receiving corticosteroids is also being treated with a
NSAID or an anticoagulant, or if the patient has a past history of
peptic ulcer disease.
I
2,26
Treatment with a proton pump inhibitor should be considered in
patients receiving dexamethasone in a dose exceeding 16mg
per day, or 16mg per day for a long interval.
I
2,26
11.4
Bone effects
Patients receiving corticosteroids have an increased risk of bone loss and fracture. The risk of fracture
is related to the dose and duration of corticosteroid treatment. Other risk factors include age, body
weight, menopausal status and a previous history of fractures. Post-menopausal women have a
threefold increase in the risk of a fracture within several months of starting corticosteroids,
independent of the baseline bone density. Randomised trials for the prevention of steroid-induced
osteoporosis have not been conducted in patients with brain tumours, but calcium supplementation
with vitamin D31, calcitonin32 and bisphosphonates31 have been effective in preventing bone loss in
patients receiving corticosteroids for other indications. Bisphosphonates provide the best protection
against corticosteroid-induced bone loss and fractures. Post-menopausal women with brain tumours
who are started on corticosteroids usually should be treated with a bisphosphonate (alendronate 70mg
per week, risedronate 35mg per week, or cyclical etidronate). Men and premenopausal women should
have a bone density measurement to assess their baseline risk of developing osteoporosis. The use of
osteoporosis prophylaxis should not be considered in patients with a very short prognosis.
Recommendation
Level
References
Prophylactic treatment for osteoporosis should be started in postmenopausal women receiving corticosteroids and in premenopausal women and men if the T score is less than -1.5. The
Australian Pharmaceutical Benefits Scheme currently approves
the use of risedronate in patients on steroids for greater than
three months with a T score of less than -1.
I
30
Patients with brain tumours receiving corticosteroids may be at increased risk of Pneumocystis
jirovecii (carinii) pneumonia. Prophylactic treatment may reduce the risk of Pneumocystis jirovecii
pneumonia, but is not recommended as routine treatment except with concurrent temozolomide and
radiotherapy.1,2
More information on corticosteroids is given in Chapter 15 Palliative care.
11.5
Skin reactions
11.5.1
Introduction
The skin of patients with gliomas can exhibit a wide and growing spectrum of cutaneous changes
attributable to the tumour and/or the growing range and combinations of specific and supportive
therapies used to manage this patient group. Cutaneous complications are highly visible, often
discomforting, and serve as a constant reminder to patients that they have cancer and that their
treatment is having toxic effects on the rest of their body and health.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
The most common cutaneous changes observed in those with gliomas are those attributable to its
treatment. Supportive care for cerebral oedema, seizures, mood disturbances and other tumour
complications are also common causes of iatrogenic adverse reactions that involve the skin.
This section focuses on a number of common and important reactions detailing their presentation,
differential diagnosis, associated toxicities, their significance and management.
11.5.2
Cutaneous drug reactions
Cutaneous changes in glioma patients can mimic other skin and multi-organ diseases. They can warn
also of associated internal changes and toxicities. Traditional alkylating agents affect rapidly dividing
cells making the skin, hair, nail matrix and mucosal toxicities common. Type A adverse reactions are
attributable to a drug’s known pharmacology and including its mechanism of action. These include
myelosuppression, mucosal erosions and ulceration including mouth ulcers and erosions plus
gastrointestinal upset, alopecia, and/or a petechial eruption which occurs as the platelet count falls to
low levels due to myelosuppression that is typically limited to dependent areas and or occurring in
areas of pressure or scratching.
Other cutaneous drug-associated reactions are classed as type B where their pathophysiology is not
well understood. These are often described as unpredictable or �hypersensitivity’ such as the common
exanthematic drug eruption (a spotty, non-confluent, red macular or slightly papular eruption that
blanches with pressure and may or may not be pruritic). The diagnosis of a drug cause is supported by
its time of onset, resolution on stopping the causative agents and its more rapid recurrence on
rechallenge.
Both type A and B reactions can affect the skin, hair, nails and mucous membranes of patients.
Although many adverse reactions to chemotherapeutic agents and anticonvulsants are solely limited to
the skin, with many asymptomatic, mild and transient eruptions, others can be severe and lifethreatening. Even a relatively mild cutaneous eruption can warn of severe internal organ toxicities. If
a serious or severe drug reaction is suspected, the early cessation of all potentially causative drugs can
reduce mortality.
Key point:
•
When a new rash occurs in patients on anticonvulsants, liver and renal function should
be checked to assess internal organ toxicity.
11.5.3
Cutaneous eruption of temozolomide and lymphocyte recovery
The frequency of rash reported in patients receiving temozolomide is close to that usually seen in
placebo control groups for many neurology and oncology conditions such as patient groups being
treated for epilepsy. The eruptions reported in association with this temozolomide have been poorly
characterised–including analysis of their timing, response to withdrawal and/or rechallenge–nor were
diagnostic skin biopsies taken. Thus their causality has not been well documented and assessed. It is
thus recommended that you follow a guide similar to that outlined for glioma patients receiving
anticonvulsant therapy.
The cutaneous eruption of lymphocyte recovery is more commonly seen in patients with leukaemia
receiving chemotherapy, but can occur in other oncology settings. This is due to the return of tissueinfiltrating activated immunocompetent lymphocytes that usually occurs 6–12 days after a
chemotherapy cycle and can be associated with a low-grade fever. The rash of lymphocyte recovery is
usually slightly itchy, transient and exanthematous in nature.
Symptom management and complications
159
11.5.4
Radiotherapy
Acute radiation skin reactions are common. This is because radiotherapy preferentially targets cells
that divide rapidly, including those of the skin and bone marrow. This is reduced by increased
fractionation, lower total doses and the use of multiple fields.
Acute cutaneous radiation effects can be minimised by the use of a soap-free emollient cleansers and
the regular application of a non-fragranced, non-irritant moisturiser. Acute radiation effects are also
known as radiation dermatitis or radiation skin reaction. They can begin within days to weeks with a
transient faint skin erythema leading to a progressive although self-limiting skin erythema. Sorbolene
is typically sufficient to relieve mild symptoms but on occasion a mild topical corticosteroid (eg 1%
hydrocortisone) could be applied to affected skin to aid with symptoms of pruritis. Ulcers can occur
but usually heal, but can recur if very high doses are given to the skin. If itchy, slightly eroded or
weeping, colloidal oatmeal containing creams and cleansers are useful along with wet compresses
using cool, slightly damp cotton towels or wraps for 30–60 minutes one to three times a day. If
insufficient, mild to moderate topical corticosteroids should only be used sparingly and for brief
courses in combination with an emollient used more generously.
Acute radiation dermatitis then usually resolves over weeks to months, usually resulting in a
temporary increase in skin pigmentation. High doses usually result in loss of hair follicles, sebaceous
along with eccrine glands. This reduces the skin’s natural moisture and leads to dry more sensitive
skin that has shed and lost its hairs. Doses over 45Gy are associated with permanent hair thinning or
loss. Recovery may take months up to one year. If the skin does not show signs of atrophy and
thinning, hair transplant can be attempted.
Over the following year the skin often becomes thinner, dryer and semi-translucent and the vessels
more easily seen. It is critical to protect areas treated with radiotherapy from sunlight as they are
subject to accelerated photo-aging and a greater risk of secondary malignancies.
Many kinds of rashes, irrespective of type and aetiology, can initially localise in areas of previous
radiotherapy, whether this be recent (hours, days to weeks, or even months to years).
11.5.5
Clinical approach to managing a rash in a glioma patient on an
anticonvulsant
Anticonvulsants carry the greatest risk of causing serious reaction in this patient group. Depending on
the agent chosen, it is important not to exceed the recommended dosing schedule; and should a rash
occur, the patient should contact their doctor. Current dosing guidelines have been designed to reduce
the risk of serious reactions. Rashes are common in this group of patients and many non-drug-related
eruptions can occur in patients on therapeutic agents. A rash during the first five days of therapy (in
the first exposure) is usually due to a non-drug cause.
Patients who develop a rash in the first few months of anticonvulsant therapy, particularly phenytoin,
carbamazepine, phenobarbitone and lamotrigine, need to be carefully evaluated. Rashes may only
become apparent when dexamethasone dose is decreased or ceased. The most common
anticonvulsant-associated eruption is an isolated, viral-like, eruptive rash usually described as
morbilliform or maculopapular in appearance. This is self-limiting; however, a clinically similar
eruption may accompany rare but more serious systemic hypersensitivity reactions.51 Thus, all
patients who develop rash during the first few months of anti-convulsant therapy should be instructed
to immediately contact their physician for consultation.
Benign drug-associated eruptions typically peak within days and progressively settle over ten to 14
days. A benign, isolated, drug-related rash is spotty, non-confluent and non-tender. There should be
only minor facial involvement and no periorbital puffiness; no facial or neck oedema; and no
involvement of the mucosal surfaces of the eye, lip, or mouth. The diagnosis of a benign rash is
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
consistent with the absence of systemic symptoms such as fever, malaise, pharyngitis, anorexia or
headache. There should be no lymphadenopathy, hepatomegaly or splenomegaly, and laboratory tests
should be normal (ie complete blood count with differential, liver function tests, urea, creatinine, and
urinary analysis). If a benign isolated rash occurs, the anticonvulsant dose should not be increased
until the rash has entirely resolved; ideally, the dose should be reduced. Patients who develop a rash
should be closely monitored and warned to contact medical staff should the rash worsen or new
symptoms emerge. Pruritis associated with a benign rash can be treated with an antihistamine and/or
topical corticosteroid. These drugs will not mask the development of a serious reaction. The
characteristics of benign rashes are also relevant to the assessment of rash in the context of
medications other than anticonvulsants including agents such as allopurinol.
Serious drug rashes are usually confluent and widespread or show prominent facial, neck, and upper
trunk involvement. Serious rashes may be tender or have a purple �purpuric’ or hemorrhagic
appearance that does not blanch with pressure. Serious drug rashes may involve mucosal surfaces.
They are accompanied or preceded by symptoms and signs of systemic toxicity such as fever, malaise,
pharyngitis, anorexia, or lymphadenopathy.15 Rashes with any feature(s) suggestive of a serious
reaction necessitate immediate drug cessation, and investigation and monitoring for internal organ
involvement, particularly in the hepatic, renal, and haematological systems. Involvement of different
organs can occasionally occur, and the severity of internal organ toxicities may increase despite drug
cessation and may necessitate hospitalisation.33 Serious reactions associated with lamotrigine should
lead to prompt discontinuation of both the suspected causal agent and any other agent that might delay
its elimination such as valproate.34 It is important that another anticonvulsant from a different noncross-reacting drug group be substituted as rapidly as possible, if immediate discontinuation is
necessary, to reduce the risk of status epilepticus. There may be cross-reactivity in terms of clinical
reactions to anticonvulsants (phenytoin, phenobarbital, carbamazepine, primidone and clonazepam).
Sodium valproate may usually be substituted safely.35 Early discontinuation of associated drug(s) after
onset of a serious reaction improves patient outcome; however, drug discontinuation may not always
prevent a more serious, life-threatening reaction from developing.20
11.5.6
Conclusions
A rash, particularly during the first eight weeks of anti-convulsant therapy, warrants evaluation by the
treating physician and/or dermatologist. If a rash shows cutaneous features of a severe reaction or is
associated with systemic symptoms, or involves mucosal surfaces, the anticonvulsant, as well as any
concomitant unnecessary medications and any that could inhibit or delay its metabolism or
elimination, should be promptly discontinued to reduce the consequences of a potentially lifethreatening reaction. Thus the clinician needs to be aware of risks, clinical features and management
of anticonvulsant-associated rashes. The decision to use an anticonvulsant in this group of patients
should be based on a risk–benefit analysis, with the rare risk of serious rash weighed against the risks
of seizures.
Recommendation
Level
References
Cutaneous drug eruptions with onset after ten days of exposure
to an anti-convulsant, if associated with mucosal involvement or
with systemic features, may be serious and require changing the
antiepileptic medication to another group or category of drugs.
III
14
Symptom management and complications
161
11.6
Venous thromboembolism
11.6.1
Introduction
Venous thromboembolism (VTE) (deep-vein thrombosis with or without its major complication,
pulmonary embolism) commonly occurs in patients recovering from a variety of surgical procedures
or in patients with incapacitating medical illnesses. Risk factors for VTE include genetic
predisposition, immobility and malignancy. Thromboprophylaxis using medications that interfere
with the normal coagulation process and with physical measures such as graded elastic stockings and
intermittent pneumatic compression reduce the risk of VTE, but pharmacological measures carry with
them an increased risk of haemorrhage, an issue that is a specific concern in the neurosurgical setting.
DVT usually starts in the calf, but by the time symptoms occur, 80% of patients have thrombus in
popliteal or more proximal veins. In patients presenting with isolated calf DVT, the risk of proximal
extension within a week has been variously assessed at 3–20%.36 Thrombosis is often asymptomatic
and resolved by the fibrinolytic system.
11.6.2
Incidence
In the general population, the annual incidence of DVT is about one per 1000, with a case fatality rate
range of 1–5%.37 The post-thrombotic syndrome, characterised by chronic pain, swelling and
occasional ulceration of the skin of the leg, occurs in up to one-third of patients who have had a
DVT.38 The incidence of VTE complicating gliomas has been estimated at 20–30%, with reported
peri-operative rates ranging widely between 2% and 60%.2 The reported incidence is highly
dependent on the sensitivity of the test used to detect VTE. The most sensitive test is a radio-labelled
fibrinogen scan, which has been reported to detect asymptomatic DVTs in 72% of meningiomas and
20% of cerebral metastases.39 Particularly high rates of DVT (11–75%) are also reported in patients
after stroke, particularly when there is residual hemiplegia.40
A systematic review41 revealed that in the first six weeks after surgery for glioma, incidence rates of
VTE range from 3% to 60% depending on the prophylactic regimen used. Beyond six weeks postoperatively, the rates of DVT ranged from 0.013 to 0.023 per patient–month of follow-up. A 24% rate
of incidence of symptomatic DVT was identified during 17 months of follow-up beyond the first six
post-operative weeks. In six studies, the presence of leg paresis, histologic diagnosis of glioblastoma
multiforme, age over 60 years, large tumour size, use of chemotherapy and duration of surgery over
four hours were identified as risk factors.41
11.6.3
Pathogenesis of VTE in brain tumours
VTE is particularly common in brain tumours due to the release of procoagulant tissue factor42 and
fibrinolytic inhibitors (such as plasminogen activator inhibitor type I43) from tumour and surrounding
cerebral tissues, producing low-grade disseminated intravascular coagulation. Higher plasma levels of
D-dimer, lipoprotein A, homocysteine, vascular endothelial growth factor (VEGF), tissue
plasminogen activator (TPA) and plasminogen activator inhibitor (PAI-1) have been identified in
patients with gliomas.
11.6.4
Diagnosis of VTE
Deep venous thrombosis
The standard of care is the duplex Doppler ultrasound. The inability to compress the vein lumen is the
principle diagnostic criterion in the interpretation of ultrasound examinations. This has replaced the
other investigations, and is particularly sensitive in the detection of proximal deep venous thrombosis,
with a lower negative predictive value for thrombosis below the knee. For proximal DVT, the
sensitivity and specificity of compression ultrasonography is 95%, falling to 70–80% for calf DVT.44
Recurrent DVT may be difficult to diagnose on ultrasound; up to 70% of patients have residual
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
abnormalities on compression ultrasound despite no evidence of recurrent disease in the year
following a DVT.45 Comparison of old and new studies may be helpful, and a negative D-dimer may
be clinically helpful (see below).
Although scanning with radio-labelled fibrinogen is the gold standard investigation, it is not routinely
available. X-ray venography is no longer used.
Duplex Doppler ultrasound is the investigation of choice for DVT
Pulmonary embolus
The diagnosis of pulmonary embolus (PE) is unsuspected until autopsy in approximately 80% of
cases. PE is fatal in fewer than 10% of patients in whom it is diagnosed, whereas undiagnosed
pulmonary emboli are fatal in approximately one third of patients. Patients who survive an acute PE
are at high risk for recurrent PE and for the development of pulmonary hypertension and cor
pulmonale.
Nuclear scintigraphic ventilation-perfusion (V/Q) scanning of the lung is indicated when the diagnosis
of PE is suspected. A screening V/Q may be performed for patients with DVT even without
symptoms of PE. A repeat V/Q scan may be appropriate before stopping anticoagulation in a patient
with irreversible risk factors for DVT and PE, because recurrent symptoms are common and a
reference �post-treatment’ V/Q scan can serve as a new baseline for comparison. In most clinical
settings a �high probability’ V/Q scan may be considered diagnostic of PE; 87% of patients reported
as having a �high probability’ V/Q scan will have a PE. Thirty percent of patients reported to have an
�intermediate probability’ V/Q scan have a PE, while 14% of patients with �low probability’ V/Q
scans will have a PE. Approximately 4% of patients with a �normal’ V/Q scan have a PE.
A CT pulmonary angiogram (spiral CT) has a low false negative rate, and detects large emboli in the
first four generations of branches of the pulmonary arteries. CT angiography may not detect
subsegmental embolism.46 CT pulmonary angiography is an acceptable alternative to V/Q scanning,
and may resolve indeterminate results.
Key point:
•
Either a nuclear scintigraphic ventilation-perfusion (V/Q) or a CT pulmonary
angiogram can be used to diagnose pulmonary embolus. A �low-probability’ V/Q
scan does not absolutely exclude the possibility of a pulmonary embolus.
The place of the D-Dimer
The D-dimer test detects the production of fibrin degradation products consequent on the conversion
of fibrinogen to fibrin. A negative D-dimer is a useful test of exclusion of VTE in combination with a
careful clinical assessment, but a positive D-dimer has relatively low specificity.48 False positive
results are common in patients with infection and cancer and in post-operative patients and the
elderly. Even increasing the cut-off level does not allow the D-dimer to be used reliably for the
diagnosis of VTE. A negative D-dimer should be used with caution if the patient has had symptoms
for more than two weeks, and if heparin has been administered prior to testing.
Recommendation
Level
References
The D-dimer, together with a careful clinical assessment, may be
used to exclude a VTE and avoid unnecessary other
investigations.
II
47
Symptom management and complications
163
Prophylaxis of VTE
Non-pharmacological approaches: Mechanical thromboprophylaxis is particularly attractive in
neurosurgery patients because of theoretical concerns about anticoagulant-related intracranial
bleeding. Graded elastic stockings, intermittent pneumatic compression (IPC) and foot-pump devices
carry no risk of bleeding. They require constant use, and compliance is difficult in the hospital and
rehabilitation setting. They are, however, considered a safe and useful adjunct to pharmacological
approaches. The mechanical approaches limit venous stasis and enhance systemic fibrinolysis. The
failure rate with mechanical prophylaxis alone in surgery in glioma patients has been reported at
between 3% and 9.5%.49,50
Pharmacological approaches: Heparin has been the mainstay of VTE prophylaxis. Aspirin is inferior
and its use is not supported by available data. Unfractionated heparin (UFH) predominantly blocks
activated thrombin (IIa). The main safety concerns are bleeding and heparin-induced
thrombocytopenia (HIT), while UFH administration requires close monitoring of the activated partial
thromboplastin time (APTT). UFH is administered intravenously as therapy for VTE or
subcutaneously as prophylaxis. Heparin-induced thrombocytopenia and thrombosis (HIT or HITT) is
characterised by a drop in the platelet count and thromboembolic events during heparin therapy–the
risk of a serious thromboembolic event is approximately 30%, and a clinical suspicion of HITT is an
indication for the immediate cessation of heparin and switch to another anticoagulant (danaparoid or
lepirudin) and warfarinisation. A HITT screen should be performed after the cessation of heparin
therapy, and urgent advice sought from a haematologist.
Low molecular weight heparins (LMWHs) are fractionated preparations of UFH restricted to the
lower range of molecular weights. LMWHs offer comparable or superior efficacy to UFH. They do
not require monitoring of the APTT and can be administered subcutaneously either once or twice
daily, with excellent bioavailability. The risk of HITT is lower than for UFH. Disadvantages include a
long half-life, irreversibility with protamine and reduced clearance in the presence of renal
impairment. The half-life of intravenously administered UFH is 45–60 minutes, while the
subcutaneous half-life of LMWH is about four hours, with some differences in the profiles of various
LMWH preparations
Warfarin: The oral anticoagulant warfarin alters the hepatic synthesis of the vitamin K-dependent
coagulation factors (factors II, VII, IX and X, and proteins C and S). The onset of action of warfarin is
slow and widely variable, and dosing must be guided by close monitoring of the prothrombin time
(standardised as the International Normalised Ratio or INR), and there are a large number of
potentially serious interactions between warfarin and other drugs. The activity of warfarin is also
modified by dietary intake. Warfarin is teratogenic in approximately 25% of cases in the first
trimester of pregnancy.
Danaparoid (Organon) can also be used for thromboprophylaxis in patients with a history of HITTS or
allergy to heparin preparations. Lepirudin, a hirudin derivative structurally unrelated to heparin, may
also be used when heparin is contraindicated.
The place of thromboprophylaxis in the management of brain tumours
The benefit of thromboprophylaxis and associate risk of intracranial bleeding has been examined in
small cohorts of patients. The pre-operative use of aspirin has been reported to reduce the incidence of
VTE in a small cohort of patients with high-grade gliomas51 but this has not been validated and is not
generally recommended.
The risk of PE in neurosurgical patients has been reported to be as high as 5%, with a mortality rate of
9% to 50%.52 The incidence of clinically overt DVT has been reported to range from 1.6 to 4%53, but
the incidence of objectively proven DVT has been estimated to range from 19 to 43% using 125Ifibrinogen to screen for DVT and from 24 to 33% in clinical trials using venography to screen for
DVT.54
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
The use of peri-operative and post-operative UFH or LMWH has been claimed to be safe in several
uncontrolled series of neurosurgical patients. In four uncontrolled cohort studies, 507 patients were
enrolled to receive anticoagulation. UFH 5000 Units was administered subcutaneously twice daily in
277 patients starting pre-operatively, and starting post-operatively in 138. The LMWH nadroparine
was administered once daily post-operatively in 97 patients. There was a cumulative incidence of
major haemorrhagic complications of 4% and a rate of reintervention of 0.4%.55–58
A double-blind randomised trial involving 307 patients undergoing neurosurgery, most of whom had
brain tumours, confirmed that patients who received 40mg of enoxaparin daily together with thighlength compressive stockings had a significantly lower rate of VTE (17%) than patients treated with
compressive stockings alone (32%)59. The frequency of major bleeding episodes was identical in the
two groups, while the incidence of minor wound haematomas was insignificantly increased in the
enoxaparin arm. Similar findings were reported by Nurmohamed et al.60 At a higher dose of
enoxaparin (30mg every 12 hours starting in the recovery room) in patients with brain tumours was,
however, associated with a high rate of intra-cerebral haemorrhage.61
A meta-analysis of prophylaxis with heparins in neurosurgery62 evaluated four randomised controlled
studies59,60,63,64 that assessed the efficacy and safety of heparin prophylaxis in elective neurosurgery.
Heparin prophylaxis resulted in a 45% relative-risk reduction of venous thromboembolic events (95%
CI 0.35–0.66; p<0.002). Nineteen major bleeding episodes were recorded in 1022 patients. None was
fatal, but heparin treatment resulted in a 71% relative-risk increase of major bleeding (95%
Confidence intervals (CI) 0.69–5.4, p=0.24). Forty-five bleeding events were observed in 1022
patients for a median incidence of 4.4%, with the use of either UFH or LMWH resulting in a 100%
relative-risk increase of bleeding events (OR 2.06, 95% CI 1.1–3.8, p= 0.02). Nineteen nonfatal
events were recorded for a mean incidence of 1.8–2.3% in the heparin group and 1.4% in the nonheparin group. Of the 12 major bleeding events that occurred in treated patients, 11 were intracranial
bleeding and one was gastrointestinal bleeding.
The number needed to treat was 7.7 for VTE and 16 for proximal deep venous thrombosis. The
number needed to harm was 102 (105 for LMWH). The overall conclusion of the study was that
LMWH and unfractionated heparin are effective for prophylaxis of VTE in elective neurosurgery
without excessive bleeding risk. On the basis of this analysis, one major non-fatal bleeding event
might be expected for every seven proximal DVTs or total 13 thrombotic events prevented.
A trial of prophylactic anticoagulation for six months65 screened 563 glioma patients but only
randomised 186 eligible patients to dalteparin or placebo. Twenty-one patients (11%) developed VTE
within six months of surgery but there was no significant difference between the treatment arms.
There were five (5%) major intracranial bleeds in the thromboprophylaxis arm compared with one
(1%) in the placebo arm (p=0.2). Thus the role of prophylactic anticoagulation remains uncertain.
Nevertheless, there may be some patients judged to be at such high risk of bleeding that the benefit of
thromboprophylaxis is likely to be outweighed by its risk, such as in intra-dural spinal cord surgery
and some intracranial surgery.
Symptom management and complications
165
Recommendation
Level
References
Peri-operative thromboprophylaxis with a LMWH is
recommended for most patients with gliomas, although
subcutaneous UFH is a reasonable alternative.
I
61
Prophylaxis is particularly appropriate for patients with high-grade
gliomas and in elderly and immobile patients.
I
41
Thromboprophylaxis should be interrupted for surgery (no LMWH
for at least 24 hours prior to surgery), resumed during the postoperative period, and continue until the patient is fully mobile.
Mechanical measures to avoid VTE are recommended as
adjunctive therapy.
III
48,49
Treatment of VTE
Less than 1% of episodes of VTE are fatal, but significant morbidity from post-phlebitic syndrome
(symptomatic chronic venous insufficiency) develops in around 30% of individuals with lower-limb
DVT. The rate of life-threatening bleeding in subjects taking warfarin is at least 0.25% per annum64
and is higher once the INR exceeds 4.0, in the elderly and in patients with specific risk factors
(including brain tumours).
Patients with brain tumours are perceived to be at increased risk of intracranial haemorrhage with
anticoagulation because of the vascularity of tumours, and this has been used as a justification for the
insertion of inferior vena caval filters instead of anticoagulation. However, Choucair et al66 reviewed a
total of 55 patients who, despite having residual tumour, received anticoagulation for at least three
months, with no instances of intracranial haemorrhage. Ruff and Posner67 retrospectively examined
103 unselected patients with malignant glioma anticoagulated with UFH (target 2.5 x control)
followed by warfarin (INR target 2.5) for 6–14 weeks for DVT. Two of the patients (1.9%) developed
intracranial haemorrhage, with one fatality, but over the same study period 2.2% of unanticoagulated
patients developed spontaneous intracranial haemorrhage.
Traditionally LMWH has been used for initial anticoagulation to cover the period during which
warfarin becomes effective, but there is evidence that LMWH may be more effective than warfarin in
preventing recurrent VTE in patients with cancer.68 In this study, comparing six months’ therapy with
dalteparin with warfarin, a hazard ratio of 0.48 for recurrent VTE was identified (p=0.002) in favour
of dalteparin, with no significant differences in the rates of either major or minor bleeding. Although
these data were not specifically derived from patients with brain tumours, continued anticoagulation
with LMWH rather than switching to warfarin is considered a reasonable approach and avoids the
difficulties of monitoring anticoagulation levels.
The appropriate duration of anticoagulation has not been studied in patients with brain tumours, and
recommendations are extrapolated from other patient groups. Anticoagulation for three months is
recommended for DVT occurring in the context of a precipitating event that has resolved (such as a
completely resected benign tumour). Patients with pulmonary emboli are generally anticoagulated for
six to twelve months. Prolongation of these intervals is appropriate in the setting of ongoing
immobility or residual tumour, which is common in patients with high-grade glioma. The role of
aspirin following the completion of anticoagulation for VTE is uncertain. VTE recurrence is generally
regarded as an indication for indefinite anticoagulation. Smoking increases the risk of VTE and
should be discouraged. Hormonal therapy (particularly high-dose oestrogen) is relatively
contraindicated in patients who have had a VTE, although there are commonly competing factors in
decision making.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
The complication rate of IVC filters in patients with brain tumours was examined by Levin et al69,
who identified a 12% rate of recurrent PE and 57% rate of IVC or filter thrombosis with recurrent
DVT or a post-phlebitic syndrome. The risk of PE is reduced by the use of concomitant
anticoagulation with IVC filters, but with a remaining risk of recurrent DVT. In patients with brain
metastases, Schiff et al70 reported a 3% cerebral haemorrhage rate with anticoagulation
(predominantly associated with over-anticoagulation) and a 40% rate of recurrent VTE requiring
anticoagulation in patients with IVC filters.
At this stage, therefore, the data support a recommendation for therapeutic anticoagulation in patients
with either gliomas or cerebral metastases with VTE rather than insertion of an IVC filter, except
perhaps in the setting of metastases with a high risk of haemorrhage (melanoma, choriocarcinoma,
thyroid and renal cancer). A CT scan to exclude intratumoural haemorrhage prior to anticoagulation is
also prudent.
Fibrinolytic agents such as streptokinase and tissue plasminogen activator may be used to dissolve
both venous and arterial thrombi and pulmonary emboli, but their use is contraindicated in the
presence of recent surgery and intracranial lesions because of an unacceptable bleeding risk.
Vena caval filters are indicated to prevent PE in patients with VTE who have a contraindication to
anticoagulation; recent neurosurgery may constitute such a contraindication. A removable IVC filter
should be used in preference to a permanent filter, with a view to conventional anticoagulation after
the post-operative period. Anticoagulation should be considered in patients with an IVC filter when a
temporary contraindication to anticoagulant therapy is no longer present. Insufficient data exist to
support a recommendation that all filter recipients should be treated with indefinite anticoagulation
regardless of their risk of recurrent thrombosis. IVC filter insertion may be considered in selected
patients with PE despite therapeutic anticoagulation. High intensity oral anticoagulant therapy or
LMWH should be considered prior to IVC filter placement, particularly in patients with
thrombophilic disorders or cancer.
Recommendation
Level
References
Anticoagulation with LMWH alone or followed by warfarinisation
(for a period depending on the clinical scenario) is
recommended as therapy for VTE in patients with gliomas.
Exceptions may include anticoagulation in the immediate postoperative period, in which case a temporary IVC filter should be
considered.
II
68
References
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19
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21
Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol
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26
Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for
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28
Vecht CJ, Hovestadt A, Verbiest HB, van Vliet JJ, van Putten WL. Dose-effect relationship of
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Davies E, Hopkins A. Good practice in the management of adults with malignant cerebral
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30
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33
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34
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lamotrigine and valproic acid. J Am Acad Dermatol 2000; 43(5 Pt 2):898–899.
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muscle vein thrombosis: rate, timing and predictors of extension. Blood 2002; 100.
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37
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al. A population-based perspective of the hospital incidence and case-fatality rates of deep
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1991; 151(5):933–938.
38
Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M et al. The long-term clinical
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39
Sawaya R, Zuccarello M, Elkalliny M, Nishiyama H. Postoperative venous thromboembolism
and brain tumors: Part I. Clinical profile. J Neurooncol 1992; 14(2):119–125.
40
Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients:
epidemiological data and efficacy/safety profile of a low-molecular-weight heparin
(enoxaparin). The Prime Study Group. Haemostasis 1996; 26 Suppl 2:49–56.
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throughout the course of malignant glioma: an evidence-based review. Cancer 2000;
89(3):640–646.
42
Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y. Expression of tissue factor
correlates with grade of malignancy in human glioma. Cancer 1996; 77(9):1877–1883.
43
Sawaya RE, Ligon BL. Thromboembolic complications associated with brain tumors. J
Neurooncol 1994; 22(2):173–181.
44
Bates SM, Ginsberg JS. Clinical practice. Treatment of deep-vein thrombosis. N Engl J Med
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approach for detection of recurrent proximal-vein thrombosis. Circulation 1993; 88(4 Pt
1):1730–1735.
46
Goodman LR, Lipchik RJ, Kuzo RS, Liu Y, McAuliffe TL, O'Brien DJ. Subsequent
pulmonary embolism: risk after a negative helical CT pulmonary angiogram--prospective
comparison with scintigraphy. Radiology 2000; 215(2):535–542.
47
Clinical policy: critical issues in the evaluation and management of adult patients presenting
with suspected lower-extremity deep venous thrombosis. Ann Emerg Med 2003; 42(1):124–
135.
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Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J et al. Evaluation of Ddimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003;
349(13):1227–1235.
49
Auguste KI, Quinones-Hinojosa A, Berger MS. Efficacy of mechanical prophylaxis for
venous thromboembolism in patients with brain tumors. Neurosurg Focus 2004; 17(4):E3.
50
Chan AT, Atiemo A, Diran LK, Licholai GP, McLaren BP, Creager MA et al. Venous
thromboembolism occurs frequently in patients undergoing brain tumor surgery despite
prophylaxis. J Thromb Thrombolysis 1999; 8(2):139–142.
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Quevedo JF, Buckner JC, Schmidt JL, Dinapoli RP, O'Fallon JR. Thromboembolism in
patients with high-grade glioma. Mayo Clin Proc 1994; 69(4):329–332.
52
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patients: a review. Neurosurgery 1994; 34(2):280–296.
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53
Levi AD, Wallace MC, Bernstein M, Walters BC. Venous thromboembolism after brain
tumor surgery: a retrospective review. Neurosurgery 1991; 28(6):859–863.
54
Agnelli G. Prevention of venous thromboembolism after neurosurgery. Thromb Haemost
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compression stockings compared with compression stockings alone in the prevention of
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60
Nurmohamed MT, van Riel AM, Henkens CM, Koopman MM, Que GT, d'Azemar P et al.
Low molecular weight heparin and compression stockings in the prevention of venous
thromboembolism in neurosurgery. Thromb Haemost 1996; 75(2):233–238.
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postoperative intracranial hemorrhage when initiated preoperatively for deep venous
thrombosis prophylaxis in patients with brain tumors. Neurosurgery 1998; 43(5):1074–1081.
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Iorio A, Agnelli G. Low-molecular-weight and unfractionated heparin for prevention of
venous thromboembolism in neurosurgery: a meta-analysis. Arch Intern Med 2000;
160(15):2327–2332.
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Melon E, Keravel Y, Gaston A, Huet Y, Combes S and the NEURONOX group Deep venous
thrombosis prophylaxis by low molecular weight heparin in neurosurgical patients.
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Cerrato D, Ariano C, Fiacchino F. Deep vein thrombosis and low-dose heparin prophylaxis in
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Perry JR, Rogers L, Laperriere N, Julian J, Geertz W, Agnelli G et al. PRODIGE: A phase III
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heparin versus a coumarin for the prevention of recurrent venous thromboembolism in
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12
12.1
PSYCHOSOCIAL CARE
Psychosocial impact of diagnosis
The diagnosis of any malignancy is distressing for the patient and their family. In the case of
malignant brain tumours, distress may be compounded by fears about the cause of the cancer, and
apprehension about loss of mental capacity: �The brain is one’s soul–to fear this loss is horrible’1.
Psychosocial research specific to brain tumours is limited compared with other cancers such as breast
and prostate cancer. If data specific to brain tumours are available this is stated in this chapter. Where
there are gaps, research data from studies of mixed cancer populations are cited where appropriate.
12.2
Psychosocial issues specific to brain tumours
12.2.1
Personality change
Personality changes may have a profound impact on carers, even if the patient is not as aware of
changes: �Sometimes it was like caring for a total stranger with only glimpses of the man he used to
be’1. Determining the precise aetiology of personality changes is difficult, with the relative
contribution of tumour location potentially being modified by surgery, chemotherapy, radiotherapy
and treatment with steroids. The concept of �organic personality change’ encompasses changes in
habitual ways of thinking and acting following cerebral insult.2
Organic personality change may be manifest as increased mental rigidity, difficulty with motivation,
changes in mood, or reduced empathy or capacity to respond to social cues. Specific focal syndromes
have also been described, such as frontal lobe syndrome which is characterised by disinhibition, overfamiliarity and poor judgment.2
Small studies have found that patients with left hemisphere lesions are more likely to experience
difficulty with communication3, while right hemisphere lesions are associated with lower scores on
facial recognition.4
12.2.2
Physical changes
Seizures are a common problem for patients with brain tumours, and limitations on driving erode the
independence of the patient, whose guilt about the added burden on family and carers may be
considerable. If seizure control is poor there may be reluctance to leave the patient unsupervised and
the patient may feel distress and grief at the necessity to be �baby-sat’ despite their adult status.
Chapter 11 Symptom management and complications contains more detail on the management of
seizures and the counselling of patients and their carers.
Physical deficits such as weakness, hemiplegia or sensory changes exert a direct influence on quality
of life and limit the capacity of the patient to function autonomously, with obvious implications for
psychological adjustment.
Despite the fact that they are not life-threatening, �little problems’ can act synergistically to cause
considerable distress, yet these are often not explored by health-care professionals.5 Changes such as
residual facial weakness, weight gain related to treatment with steroids, or hair loss in a patient with
stable disease may not be seen as serious by clinicians, but can be a source of anxiety and distress for
the patient who perceives these changes to be highly socially visible.
12.2.3
Cognitive changes
It comes as no surprise that a tumour in the brain can cause disruption to brain function, and moreover
that such disruption of brain function can give rise to changes in emotions, behaviour and cognition.
The mechanisms by which brain tumours can compromise brain function include invasion or
Psychosocial care
173
displacement of brain tissue causing focal symptoms, disconnection of a given region of brain from a
more distant region or disruption of widely distributed networks, production of generalised symptoms
associated with raised intracranial pressure, seizures, abnormal hormones or disrupted endocrine
function6 and psychological distress. Added to these are the cognitive impairments associated with
treatment.7
Brain tumour patients can present free of neurological symptoms, with subtle and variable cognitive
impairment8, or with disabling symptoms such as marked long-term memory deficits9. Patients with
unequivocal cognitive impairment present with a wide range of heterogeneous cognitive impairments,
however, strong associations between cognitive function and tumour location have been reported,4
although tumour histology has been shown to be a poor predictor of cognitive impairment.10 Others
have also emphasised the importance of patient characteristics such as age11 and premorbid
intelligence and adaptive functioning12. One study of 701 patients with high-grade brain tumours
reported that factors such as older age, poorer performance status and subclinical tumour progression
may be more significant factors affecting cognitive function than radiotherapy or chemotherapy.13
The role of neuropsychological assessment is to characterise the nature and extent of cognitive
dysfunction associated with a tumour, to provide a pre-therapy baseline against which future change
can be measured, whether improvement resulting from treatments, therapies and rehabilitation, or
decline associated with treatment side effects or tumour progression. Once the patient’s cognitive
strengths and weaknesses are known, this information can be used to develop recommendations and
strategies for exploiting strengths to minimise the impact of weaknesses on daily functioning, and to
assist in providing recommendations about capacity to return to a variety of roles including those of
worker, driver, parent/caregiver, and even decision maker (testamentary capacity).
Recent studies have suggested that measures of cognitive function also have utility in predicting
tumour recurrence when tumour-specific indices (with known structure–function association with the
patient’s tumour location) are examined.14 Moreover, there is evidence that cognitive changes are
evident before structural changes are seen on imaging.15 In addition, one study found that measures of
cognition, particularly verbal memory, were independently and strongly related to survival in patients
with recurrent tumours.16 In another patient series, cognitive function was found to be predictive of
survival but only in the older patients.17
Although cognitive dysfunction is common in patients with brain tumours, many studies report
relatively insensitive outcome measures–such as performance status or IQ scores–that fail to measure
such disabling difficulties as impairment in executive function18, so it is difficult to quantify the extent
of the problem.
12.3
Assessment of cognition
It seems clear that if the goal is to detect the cognitive effects of these anatomically heterogeneous
patterns of disease, a screening or brief assessment approach will not suffice and a more sophisticated
and detailed assessment by a person with appropriate neuropsychology training is required11,17,20 .
Recommendation
Level
References
Cognition dysfunction may not be apparent during brief
consultations, and debilitating deficits will often only be detected
by formal neuropsychological assessment undertaken by a
trained health professional.
IV
14,15,17,19
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Information gathered through interview and observation provides essential information to supplement
the results of formal neuropsychological tests. Information should be obtained from both the patient
and an independent source regarding noted and observed changes in cognition, mood and personality,
with reference to day-to-day functioning and normal occupations, including the onset and course of
each symptom. Discrepancies between patient self-report and informant observation are suggestive of
limitations in patient insight, with implications for increased carer burden.
While individual practitioners use a variety of psychometric tests, the following parameters should be
assessed:
•
estimated pre-morbid intellectual abilities
•
assessment of current intellectual abilities (including verbal and visuospatial abilities)
•
attention regulation
•
new learning and memory
•
executive and adaptive skills (such as planning and organising thoughts and actions, complex
reasoning and problem solving, initiation, impulse control, perseveration, sequencing, use of
feedback/errors, social judgement, insight and self appraisal, speed/efficiency of information
processing)
•
mood and emotional functioning (including behaviour regulation during assessment)
•
level of effort.
The process of forming a neuropsychological opinion involves interpretation of the psychological test
results with due consideration of the following:
•
the patient’s pre-morbid ability (with reference to developmental, educational, and occupational
attainments)
•
level of application or effort
•
psychosocial history
•
cultural and linguistic background
•
psychiatric and medical history
•
mood and emotional functioning (especially, but not only, in terms of reaction and adjustment to
diagnosis)
•
pain and fatigue
•
sensorimotor integrity
•
current medications
•
alcohol and/or drug use
•
psychometric issues such as the quality of normative (preferably Australian) data and practice
effects (if repeated assessment)
Psychosocial care
175
12.3.1
Subjective versus objective measures of cognitive dysfunction
While undeniably important in terms of understanding a patient’s experience of their dysfunction,
subjective complaints of cognitive impairment have been shown to be more strongly associated with
emotional distress and fatigue than objectively measured cognitive impairment in cancer patients.21 It
has been suggested that brain tumour patients, especially those with frontal system tumours, may be
especially at risk for under-reporting impairment due to impaired awareness and insight.7
Executive and adaptive dysfunction
Impairments of executive and adaptive functioning are common where brain tumours are located in
the frontal lobes or in one of the numerous regions with rich connections to the frontal lobes.22
When tumours invade the frontal lobes or frontal system networks, patients can present with
significant behavioural changes and subtle impairment of social or emotional functioning without
obvious intellectual decline. Such patients may present well in brief interviews, perform entirely
adequately on assessment of basic intellectual skills12 and abilities, and perform very well on
screening assessments such the Mini Mental State Evaluation (MMSE)23. In such patients, more
sophisticated neuropsychological assessment of executive and adaptive functioning often reveals
profound impairments in planning and organising, impulse control, initiating and carrying out goaldirected behaviour.24 Such impairments, which can disrupt a diverse range of functions that are most
identifiable as human, can have a devastating effect on the lives of patients and patients’ support
network alike.25
Recommendation
Level
References
Health professionals should consider the need for formal
neuropsychological assessment to determine the nature of
cognitive deficits and provide a basis for recommendations
regarding capacity to return to previous roles, and to assist the
patient and their family to adjust.
IV
17
Competence and decision-making
Given the often poor prognosis, making informed treatment choices and planning for future care is
important. However, there is some evidence that patients and their families may not always be open in
communication, and few couples openly discuss death and dying although in some instances there
may be a mutual unexpressed understanding of the situation.26
Legally, an adult patient is able to make a decision regarding medical treatment if they have the
ability to understand the nature and the consequences of their decision. It is up to the treating
practitioner to determine whether a patient is competent to make a treatment decision. A patient may
be legally competent to make some decisions but not others, depending on the extent of their
cognitive impairment. The more serious the consequences of the decision, the greater degree of
competence required. Thus a patient may be competent to consent to a minor form of treatment but
not competent to make a decision to consent to the withdrawal of life support. If the treating
practitioner is in any doubt about a patient’s competence they should seek another opinion from
another suitably qualified practitioner.
A competent adult patient has an absolute right to refuse medical treatment, including potentially lifesaving treatment. A patient’s refusal may be for whatever reason the patient chooses even if the
decision may lead to the patient’s death. It does not matter if the health professionals involved in the
patient’s treatment, family members or anyone else considers the refusal to be unreasonable,
irrational, or not in the patient’s best interests. The presumption of competence will not be overridden
because the patient’s decision to refuse medical treatment will lead to their death. To provide
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
treatment to a competent patient against his or her express wishes amounts to assault and leaves a
health-care professional vulnerable to legal action.
Key point:
It is up to the treating practitioner to determine whether a patient is competent to make a
treatment decision.
Recommendation
Level
References
A medical practitioner must provide the patient with information
to allow the patient to make an informed decision about
treatment. A patient must be advised about the nature of their
condition, any alternative forms of treatment that may be
available, the consequences of those forms of treatment, and
the consequences of remaining untreated.
I
27
A competent adult patient may express an intention in an advance directive to refuse medical
treatment in the future at a time when he or she may no longer be competent to make a treatment
decision. At the time of making the advance directive the patient must be mentally competent and
properly informed about the consequences of the directive, and the advance directive must apply to
the clinical circumstances existing at the time the directive is sought to be relied upon. Advance
directives have been given express statutory recognition in the ACT, Northern Territory, Queensland
and Victoria. More information is given in Chapter 15 Palliative care.
If a medical practitioner believes a patient is cognitively impaired and is not capable of making a
treatment decision and there is no valid advance directive, the medical practitioner has a legal
responsibility to obtain consent for the proposed treatment from a surrogate decision-maker. The most
significant exception to this is the provision of urgent medical treatment. Although the definition of
�urgent’ varies from State to State, the common thread is that the medical practitioner must believe
that the medical intervention is necessary to save the life of the person or to prevent serious damage to
the person’s health, or to relieve a patient’s suffering from or continuing to suffer from significant
pain or distress. In South Australia and the Northern Territory this decision must be based on the
opinion of at least two medical practitioners, although in South Australia, one practitioner will suffice
if it is impractical to have a second practitioner involved.
NSW, Victoria, Tasmania, Western Australia, South Australia and Queensland have legislation
enacted to enable the �person responsible’ or the �statutory health attorney’ (Queensland) to give
consent for medical or dental treatment. The �person responsible’ is defined in the relevant legislation
and may include a spouse, a near relative, a close friend or primary carer of the patient. The
legislation in each State also provides a hierarchy that must be followed before the next person in the
hierarchy is authorised to give consent on behalf of the patient. The hierarchy and any other
prescribed steps must be followed.
The process of obtaining consent from the person responsible (the surrogate decision-maker) still
requires the practitioner to provide such information to that person to enable that person to make an
informed decision. However, the legislation does not enable the person responsible to give consent for
medical or dental treatment that is classified under the legislation as �special’ (NSW, TAS, WA, VIC,
QLD) or �prescribed’ (SA, ACT) treatment. Special or prescribed treatment includes procedures such
as sterilisation, termination of pregnancy or experimental procedures. All Australian States prohibit
the performance of this type of surgery or procedure without the consent of the relevant statutory
body. The Northern Territory (unlike other States) defines this category of procedures as �major
Psychosocial care
177
medical’ procedures. In several States it is an offence punishable by fine or imprisonment to provide
this type of medical or dental treatment, other than in accordance with the relevant legislation. The
Victorian legislation provides that any medical practitioner who carries out this category of treatment
other than in accordance with the legislation may be guilty of professional misconduct.
The Australian Capital Territory and the Northern Territory do not have a provision to enable a near
relative, spouse or carer to give consent on behalf of person with cognitive impairment. Therefore, the
appropriate person to provide consent is the person legally appointed as guardian under the relevant
Act. If no guardian has been appointed, and the treatment does not fall under the definition of �urgent'
medical treatment, the medical or dental practitioner should not provide treatment until the
appropriate steps have been taken to have a guardian appointed as required by the legislation.
Several States have included in their guardianship legislation a provision to enable some treatment to
be provided without consent of the patient or the �person responsible’ as long as the prescribed steps
set out in the relevant Act are followed. For example in NSW, if the guardian or person responsible
cannot be located, a medical practitioner may provide �minor treatment’. This is defined under the
NSW legislation as being treatment that will most successfully promote the patient’s health and
wellbeing and the patient does not object to the treatment being administered. The treating practitioner
must certify these matters in the patient’s record and state that the treatment is necessary. Minor
treatment is considered to be treatment that will not cause any distress or is of a temporary nature and
the benefit of the treatment will outweigh the side effects of the intervention. For example, in NSW
this includes the giving of a general anaesthetic or other sedation to manage a fracture or dislocation
or the administration of medications that affect the central nervous system for the purpose of
providing an analgesic, anti-pyretic or antihistamine. The legislation in Tasmania, Queensland and
Victoria also has provisions allowing for minor treatment to be carried out in certain circumstances.
The variations between each State are such that it is impossible to cover all of the issues here. Healthcare professionals and medical practitioners in particular who regularly deal with patients with a
cognitive impairment should be aware of the legislation that applies in their State or Territory. If there
is any doubt about a particular case, legal advice should be obtained.
For decisions at the end of life for cognitively impaired patients, it is not clear in some States or
Territories whether the relevant statutory body is legally empowered to make decisions to withhold or
withdraw life-sustaining treatment, where there is no valid advance directive or surrogate decisionmaker.
In these circumstances, a medical practitioner’s obligation is to treat the patient in accordance with the
patient’s best interests. In forming a judgement as to what is in the best interests of the patient, factors
to be taken into account by the medical practitioner include the personal circumstances of the patient,
and information from family and/or carers about the choice the patient might have made in the
circumstances. In decisions at the end of life it is reasonable to take account of the invasiveness of the
treatment and the indignity to which a person has to be subjected if life is prolonged by artificial
means.
A medical practitioner is not required to provide treatment that is futile or treatment that is not
clinically indicated, nor is there any obligation to prolong the life of a dying patient by any means
available regardless of the quality of the patient’s life. There may be differing views about the futility
of treatment. In the case of a dispute about a patient’s treatment between a patient’s family and healthcare professionals, an application may be made to the court by either party to resolve the dispute. The
Supreme Courts in each State and Territory have the power to act in the welfare of a person who is
unable to care for themselves. The Court can make decisions for incapable persons in their best
interest, including a decision to cease life-sustaining treatment.
The legal requirements for competent decision-making also apply to a patient’s decisions about
financial matters, both during their remaining life and after they die. The various State and Territory
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
statutory bodies are able to make decisions about a patient’s financial matters where they are not
competent to do so and the patient has no guardian or has not assigned power of attorney.
The ability to make a valid Will depends on a patient having the required testamentary capacity to do
so. In general terms, to have testamentary capacity, the patient must:
•
Understand the nature and the effect of the Will.
•
Understand the extent of the property they are disposing by the Will.
•
Comprehend and appreciate those who should be considered as their beneficiaries.
•
Not have a disorder of the mind that �shall poison his affections, pervert his sense of right, or his
will in disposing of his property and bring about a disposal of it which, if his mind had been
sound, would not have been made’. 28
The relevant legislation in each State and Territory is:
NSW
Guardianship Act 1987
SA
Guardianship and Administration Act 1993
Consent to Medical Treatment and Palliative Care Act 1995
TAS
Guardianship and Administration Act 1995
WA
Guardianship and Administration Act 1990
QLD
Guardianship and Administration Act 2000
Powers of Attorney Act 1998
NT
Adult Guardianship Act
Powers of Attorney Act
Emergency Medical Operations Act, 1992
Natural Death Act 1988
VIC
Guardianship and Administration Act 1986
Medical Treatment Act 1988
ACT
Guardianship and Management of Property Act 1991
Medical Treatment (Health Directives) Act 2006
Recommendation
Level
References
Health professionals should determine the capacity of the
patient to make decisions, and be aware of legislation that
applies in the case of patients who are not competent to make
decisions. Health professionals should be prepared to review this
capacity as it may change over time.
I
27,29
Psychosocial care
179
12.3
Quality of life
A study of 50 patients with primary brain tumour found that quality of life was affected by a number
of factors: the extent of tumour involvement (with bilateral involvement leading to worse quality of
life than unilateral), poor performance status, being female, having been divorced, undergoing
aggressive treatment, and being unable to work.30 Motor deficits, confusion and dysphasia have also
been found to reduce quality of life.31
Patients with tumours in the anterior right hemisphere have been reported to have higher quality of
life.32 Freedom from depression, having an active social life and level of energy, and fewer symptoms
are also associated with higher quality of life.33
In addition to the direct impact of the tumour and surgical treatment, other treatments such as
radiotherapy can affect quality of life. A prospective study reported that 42% of patients experienced
considerable tiredness after radiotherapy.34
There are few data about the quality of life of patients who survive brain tumours for extended
periods. In 57 patients with stable disease, quality of life was found to be related to depressed mood,
anxiety and performance status.35 One study of ten patients who had survived glioma for five years
found that only one patient was working full-time, and impairments in attention, role functioning and
capacity to participate in leisure activities were prominent in nearly all patients.36
Quality of life for patients with recurrent disease is determined by multiple factors, and is poorer than
in those with stable disease. The existential issues confronting patients and their families are
considerable, but often not expressed.37 Cognitive deficits were universal in a study of 94 patients, and
anxiety was higher in those more recently diagnosed with recurrence.38 Interviews about quality of
life with bereaved relatives reveals that cognitive and personality change exert a powerful influence
on their appraisal of quality of life for patients with advanced disease.39
When faced with a poor prognosis, patients may use alternative therapies in the belief that
conventional medicine is �not very effective’. A study of 167 patients with primary brain tumour
found that 24% used alternative therapies, and of these patients, two-thirds believed that the therapies
were useful in terms of improving their energy, or physical or mental wellbeing. This study did not
find any difference in quality of life between users of alternative therapies and non-users.29 Use of
alternative therapies is described in more detail in Chapter 10 Alternative, complementary and
unproven treatments.
Key point:
•
Cognitive and personality changes are common and have a powerful adverse impact
on quality of life.
12.4
Psychological disorders
12.4.1
Anxiety and depression
Extent of the problem
Half of patients treated for primary brain tumour self-report depressed mood.33 Twenty-eight percent
of a sample of 89 ambulatory patients with brain tumours met Diagnostic and Statistical Manual of
Mental Disorders (DSM IV) criteria for depression. The Glioma Outcomes Project analysed data from
598 patients in the early post-operative period. There was a marked disparity between patient selfreports of depression and physician assessment of depression (93% versus 15%), and even when
physicians considered that the patient was depressed, few patients were referred for specialist
treatment.22 Those patients who were identified as depressed by their physician had significantly
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
shorter survival than those not identified as depressed, and more post-operative complications. At sixmonth follow-up, patients being treated with corticosteroids were more likely to be depressed than not
depressed.22
Risk factors for anxiety and depression
There is some evidence about factors that may predispose to the development of depression in patients
with brain tumours. Females have been reported to have higher scores on measures of anxiety and
depression than males40,41, and those with left hemisphere lesions have higher depression scores than
those with right hemisphere lesions. Frontal location of tumour has been found in one study to be a
risk factor for depression, along with having a family history of depression.42 Not surprisingly, high
levels of physical disability and cognitive dysfunction are associated with high levels of psychological
morbidity.43
The general cancer literature has identified a number of risk factors for the development of anxiety or
depression, and it is worthwhile to document these factors with a view to referral for specialist
psychosocial assessment and treatment, and early identification and intervention.
Table 12.1
General risk factors for increased psychosocial distress
Characteristics of the individual
Characteristics of the disease and treatment
Female
Younger (less than 55 years of age)
Single, separated, divorced or widowed
Living alone
Children younger than 21 years
Economic adversity
Lack of social support, perceived poor social
support
Poor marital or family functioning
History of psychiatric problems
Cumulative stressful life events
History of alcohol or other substance abuse
At the time of diagnosis or recurrence during
advanced stage of disease
Poorer prognosis
More treatment side-effects
Greater functional impairment and disease
burden
Experiencing chronic pain
Fatigue
Adapted from Clinical Practice Guidelines for the Psychosocial Care of Adults with Cancer 2003. Reproduced with
permission.44
Recommendation
Level
References
Patients who have risk factors for increased psychological distress
should be offered referral for psychosocial treatment as this
minimises the likelihood that they will develop significant distress
I
45
Anxiety versus a disorder
Anxiety is a feeling of apprehension and worry. In the context of a brain tumour, anxiety is often
related to the prognosis, treatments and symptoms. While some degree of anxiety is normal in
response to the diagnosis, a disorder should be considered when the distress interferes with the
capacity of the person to make treatment decisions or undergo treatment (such as having panic attacks
when attending for radiotherapy treatments), or it interferes significantly with sleep and appetite,
social and occupational functioning. Similarly, a diagnosis of depression should be considered when
mood is severely and pervasively depressed, there is inability to enjoy normally pleasurable activities,
Psychosocial care
181
or there is an adverse impact on social and occupational functioning. Depression may also be
associated with decreased energy, feelings of worthlessness or guilt or recurrent thoughts of death or
suicide.44
Unfortunately patients may be reluctant to express symptoms of anxiety or depression because of
concern that this makes them appear weak or ungrateful, so health professionals may need to ask
specific questions to elicit symptoms. The following suggested prompts are adapted from Clinical
practice guidelines for the psychosocial care of adults with cancer:44
•
Can you tell me how the diagnosis has affected you emotionally?
•
Are there any particular things that make you anxious? How would you say this is affecting
your life?
•
Would you say that you have felt really sad or depressed?
Treatment
The approach to treatment of anxiety and depression in patients with cancer generally involves a
combination of pharmacotherapy and psychotherapeutic support.46 Specific psychological therapies
are listed in the Table 12.2 below, along with documentation of their effectiveness. Further
information about treatment of distress is available in Clinical Practice Guidelines for the
Psychosocial Care of Adults with Cancer, which can be downloaded from
<www.nhmrc.gov.au/publications/synopses/cp90syn.htm>.
The pharmacological treatment of anxiety may include use of antidepressant medication, neuroleptics,
and benzodiazepines. For acute anxiety, benzodiazepines are often helpful; with the shorter-acting
agents such as lorazepam and oxazepam being safest although they may be associated with a risk of
break-through anxiety.47 Antidepressant medication is generally well-tolerated and effective in
patients with cancer.48
While clinical experience suggests that antidepressant medication may be of benefit in patients with
brain tumours49, it is particularly important to be aware of the risk that antidepressant medication may
lower seizure threshold in this population.
Key point:
Identification of depression and anxiety is important as these disorders can be effectively
treated with a combination of supportive psychotherapy, cognitive and behavioural
techniques, and pharmacotherapy
Delirium
Delirium is a syndrome of cognitive disturbance and affective arousal, common in patients with
cancer, but often misdiagnosed and mistreated. Patients may experience disturbances in a variety of
functions including level of consciousness, attention, thinking, perception, emotion, memory,
psychomotor behaviour and sleep/wake cycle, the pattern of disturbance typically fluctuating over the
course of a day.47 Delirium occurs in between 15 and 20% of hospitalised cancer patients, although
the figure appears to be much higher in those with advanced disease.47
Whilst the agitated, disruptive patient is likely to attract the attention of health professionals,
hypoactive cases, which account for up to 50% of cases of delirium, may go undetected or be
misdiagnosed as depression.50 Agitated disruptive behaviour due to delirium may similarly be
misdiagnosed as anxiety or personality disorder. The experience of delirium is highly distressing for
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
patients and their families, with over half of patients recalling their delirium experience, which is
often characterised by disturbing psychotic symptoms.51
Key point:
•
Delirium should be suspected in any patient who demonstrates an abrupt change in
behaviour, personality or mood.
The treatment of delirium focuses on identification and treatment of the underlying causes, along with
attention to fluid and electrolyte balance, nutrition, and measures to help reduce anxiety and
disorientation, such as constant re-orientation, use of a night light, correction of hearing and visual
impairment.52 Pharmacological treatment of delirium has traditionally been with low-dose typical
antipsychotic medications such as haloperidol which, while effective, carry the risk of extrapyramidal side-effects.47 There are few well-designed studies examining the use of the atypical
antipsychotics in delirium, however risperidone and olanzepine appear to be safe and effective.50
Recommendation
Level
References
When delirium is suspected, the cause must be identified urgently
and treatment of the cause must take place while
pharmacological and non-pharmacological treatments are
initiated to reduce the distress of the patient and their family.
IV
46
Organic mental disorders
Patients may experience mental disorders without the clouding of consciousness that is central to a
diagnosis of delirium. In these instances, prominent symptoms include anxiety, mood disturbance and
hallucinations, and sometimes delusions.43 Organic mental disorders can be due to the direct effect of
the brain tumour and local oedema, or indirect effects of disease or of treatments such as
corticosteroids, or a combination of these factors. Management involves investigation and treatment
of the cause as appropriate, as well as treatment of the psychotic symptoms with antipsychotic
medication such as risperidone 0.5mg/day, titrating up to 4–6mg/day depending on clinical response
and side-effects. On rare occasions, patients may require inpatient management in a psychiatric unit as
an involuntary patient because they lack insight and the nature of their condition means that they pose
a risk to themselves or others.
Recommendation
Level
References
If organic mental disorder is suspected, the patient must be
assessed for treatable causes, and specialist psychiatric advice
obtained about management.
IV
46
12.5
Issues facing families and carers
Levels of distress in the relatives of 75 patients with brain tumours have been reported as higher than
the levels of distress amongst patients themselves. 34
Family members can feel isolated from others who fail to appreciate the burden of care they are facing
when the patient has personality or cognitive deficits53, and this makes it harder to cope54. In one
study of the adjustment of 95 caregivers of patients with malignant brain tumours, 88% reported that
the patient experienced at least one neuropsychiatric symptom, the most common being dysphoria or
depression. Levels of depression in caregivers were linked with the number of neuropsychiatric
Psychosocial care
183
symptoms experienced by patients.55 Whilst assisting patients with activities of daily living does pose
a burden on schedules and health, this does not affect the mood of caregivers in the way that
neuropsychiatric symptoms do.55 This is consistent with research demonstrating that even after
bereavement, very few relatives considered that quality of life for the patient had been good or
acceptable, irrespective of the time lived without severe physical disability, if the patient initially
experienced marked psychological change or distress.39 If the patient’s quality of life is poor, carers
may feel ambivalent about the patient’s survival, but such feelings may be a source of guilt.56
There may be substantial differences between patient and caregiver perception of difficulties. One
small study found that in one-third of cases, the patient and caregiver disagreed about the extent of
residual problems.57 Thus it may be difficult to maintain a balance between supporting and assisting
the patient and �taking over’.5 Relatives may see their role as remaining strong in order to protect the
patient. In some instances relatives may try to avoid explicit discussion about the prognosis because
of the belief that this would be harmful for the patient.34 Contrary to popular belief, in general,
expression of thoughts and feelings helps patients and their families cope.58
The inevitable changes in roles and relationships cause tension and distress.59,60 Relatives may
struggle to adjust to the changed personality of the patient, but find that there is little external
recognition of the grief this poses.61 Lack of support exacerbates role strain for families and carer,
who often have little respite from their caring role.1
Relatives describe difficulty in obtaining medical information and making informed treatment
choices, and express the need for discussion about quality-of-life issues in making treatment decisions
along the continuum of treatment, not only when no further treatment options exist: �Quality of life is
only raised when there is no quantity’53.
(For further discussion of issues facing carers see Chapter 2 Approach to the patient.)
Key point:
•
The contribution of patient neuropsychiatric symptoms and personality changes to carer
distress may outweigh the burden posed by physical symptoms. Patient personality
changes can lead to social isolation that compounds distress.
Needs of children
Although parents often feel tempted to avoid discussion about the seriousness of the condition62 there
is evidence that avoidance of discussion about parental cancer compounds distress in children63. The
Cancer Council NSW has developed a resource for parents to guide them in discussions with their
children about cancer: �When a parent has cancer: how to talk to your kids’.64 This resource provides
suggestions about strategies for discussion with children, including practical examples specific to
different developmental stages.
Recommendation
Level
References
Patients and their families should be informed that in general,
talking about their feelings improves adjustment.
II
58
12.6
Psychosocial interventions
Internationally, it is recognised that patients with cancer should have access to psychosocial care in
the context of a multidisciplinary team.65 In a review of quality of life in patients treated for brain
tumours, Heimans and Taphoorn66 emphasise the importance of involvement of a multidisciplinary
team in management, including access to psychosocial services. There is little literature describing
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
rigorously evaluated psychosocial interventions specific to patients with brain tumours, however in
the general cancer population, there is high-level evidence of the benefits of psychosocial
interventions, as indicated in Table 12.2 below.
Table 12.2
Psychosocial interventions and their impact on patients with cancer
Type
Description/benefits
Level of evidence
Cognitive
behavioural
therapy
Teaches skills in problem-solving, reframing attitudes, for
example, challenging �black and white’ thinking, coping
with stress and anxiety.
Relaxation therapy, guided imagery or cognitive skills
might be used to deal with stressful situations such as
particular treatments, or to reduce nausea associated with
chemotherapy.
Improvement in emotional distress, coping, anxiety,
depression and psychiatric morbidity.
Level I 67,68
Level II 45,69
Supportive
psychotherapy
Encourages the expression of emotion; validates the
experiences of the individual and offers support through
empathic listening, encouragement, and provision of
information.
Reflects on the strengths of the individual and encourages
use of adaptive coping techniques.
Improvement in mood, coping, and physical and functional
adjustment.
Level I 67,68
Group therapy
Places emphasis on sharing of experiences among patients
with comparable disease. Participants feel that their
experiences are validated, and that they can contribute in a
meaningful way to the wellbeing of other members of the
group.
Improvement in mood, coping and adjustment, anxiety and
depression.
Level I 70
Adapted from Clinical Practice Guidelines for the Psychosocial Care of Adults with Cancer 2003. Reproduced with
permission.44
Experienced clinicians highlight the importance of empathy and support, and the provision of
information about coping with specific problems, including attention to symptom control.56 Family
members also may find it helpful to be given practical information such as the fact that singing and
whispering may be intact in patients who cannot speak normally.56
The role of specialist oncology nurses is well established in some areas, and initial assessment of the
role of a specialist neuro-oncology nurse suggests a potential role in provision of information and
support, and in maintaining continuity of care for patients and their families.71 Given the practical
difficulties experienced by patients who may be unable to drive, different models of follow-up have
been explored. One study examined telephone consultation follow-up conducted by an oncology
nurse. Patients were generally satisfied with this method of follow-up, although the authors noted the
tendency of patients to downplay symptoms, and this may be a disadvantage if carers feel that they
are not as actively involved in follow-up.72
Support groups can be helpful through a number of mechanisms, including validation of the patient’s
experience and provision of the opportunity for patients to express their worst fears while also hearing
about coping strategies of others.5 Carers and patients may cope through reappraising and redefining
their situation, and believing in their own personal strength.54
Psychosocial care
185
However for many patients and their families there remains a gap between perceived psychosocial
needs and the support offered within clinical services.73 This is consistent with a study of 12 patients
and relatives two years after diagnosis of glioma, in which only one patient was able to resume work
comparable to that undertaken prior to the diagnosis, but none of the patients had been referred for
rehabilitation.57
Recommendation
Level
References
Patients and their carers should be asked about their emotional
adjustment and given information about available support
groups and specialist services, as these have been demonstrated
to be effective in reducing distress.
I
45,66,67
12.6.1
Referral for specialist care
Patients or family members experiencing significant psychological distress or who have severe
symptoms impacting on quality of life may benefit from referral for specialist interventions. Early
referral may reduce the risk of developing significant psychological distress.70 Appropriately trained
social workers, psychologists or psychiatrists can offer a variety of effective treatments ranging from
provision of information and support to cognitive behaviour therapy or pharmacotherapy.
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29
Verhoef MJ, Hagen N, Pelletier G, Forsyth P. Alternative therapy use in neurologic diseases:
use in brain tumor patients. Neurology 52(3):617-22, 1999.
30
Weitzner MA, Meyers CA, Byrne K. Psychosocial functioning and quality of life in patients
with primary brain tumors. Journal of Neurosurgery 84(1):29-34, 1996.
31
Osoba D, Aaronson NK, Muller M, Sneeuw K, Hsu MA, Yung WK et al. Effect of neurological
dysfunction on health-related quality of life in patients with high-grade glioma. Journal of
Neuro-Oncology 34(3):263-78, 1997.
32
Giovagnoli AR, Tamburini M, Boiardi A. Quality of life in brain tumor patients. Journal of
Neuro-Oncology 30(1):71-80, 1996.
33
Mackworth N, Fobair P, Prados MD. Quality of life self-reports from 200 brain tumor patients:
comparisons with Karnofsky performance scores. Journal of Neuro-Oncology 14(3):243-53,
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34
Davies E, Clarke C, Hopkins A. Malignant cerebral glioma--II: Perspectives of patients and
relatives on the value of radiotherapy. BMJ 313(7071):1512-6, 1996.
35
Giovagnoli AR. Quality of life in patients with stable disease after surgery, radiotherapy, and
chemotherapy for malignant brain tumour. Journal of Neurology, Neurosurgery & Psychiatry
67(3):358-63, 1999.
36
Steinbach JP, Blaicher HP, Herrlinger U, Wick W, Nagele T, Meyermann R et al. Surviving
glioblastoma for more than 5 years: the patient's perspective. Neurology 66(2):239-42, 2006.
37
Adelbratt S, Strang P. Death anxiety in brain tumour patients and their spouses. Palliative
Medicine 14(6):499-507, 2000.
38
Giovagnoli AR, Silvani A, Colombo E, Boiardi A. Facets and determinants of quality of life in
patients with recurrent high grade glioma. Journal of Neurology, Neurosurgery & Psychiatry
76(4):562-8, 2005.
39
Davies E, Clarke C. Views of bereaved relatives about quality of survival after radiotherapy for
malignant cerebral glioma. Journal of Neurology, Neurosurgery & Psychiatry 76(4):555-61,
2005.
40
Pringle AM, Taylor R, Whittle IR. Anxiety and depression in patients with an intracranial
neoplasm before and after tumour surgery. British Journal of Neurosurgery 13(1):46-51, 1999.
41
Mainio A, Hakko H, Niemela A, Koivukangas J, Rasanen P. Gender difference in relation to
depression and quality of life among patients with a primary brain tumor. European Psychiatry:
the Journal of the Association of European Psychiatrists 21(3):194-9, 2006.
42
Wellisch DK, Kaleita TA, Freeman D, Cloughesy T, Goldman J. Predicting major depression in
brain tumor patients. Psycho-Oncology 11(3):230-8, 2002;-Jun.
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Anderson SI, Taylor R, Whittle IR. Mood disorders in patients after treatment for primary
intracranial tumours. British Journal of Neurosurgery 13(5):480-5, 1999.
44
National Breast Cancer Centre, National Cancer Control Initiative. Clinical practice guidelines
for the psychosocial care of adults with cancer. 1-242. 2003. Canberra, NHMRC National
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European Journal of Cancer 27(2):170-4, 1991.
46
Sellick SM, Crooks DL. Depression and cancer: an appraisal of the literature for prevalence,
detection, and practice guideline development for psychological interventions. PsychoOncology 8(4):315-33, 1999;-Aug.
47
Breitbart W. Identifying patients at risk for, and treatment of major psychiatric complications of
cancer. Supportive Care in Cancer 3(1):45-60, 1995.
48
Chaturvedi SK, Maguire P, Hopwood P. Antidepressant medications in cancer patients. Psychooncology 1994; 3:57-60.
49
Junck L. Supportive management in neuro-oncology: opportunities for patient care, teaching,
and research. Current Opinion in Neurology 17(6):649-53, 2004.
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empirical literature. Palliative & Supportive Care 3(3):227-37, 2005.
51
Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and deliriumrelated distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses.
Psychosomatics 43(3):183-94, 2002;-Jun.
52
Stagno D, Gibson C, Breitbart W. The delirium subtypes: a review of prevalence,
phenomenology, pathophysiology, and treatment response. Palliative & Supportive Care
2(2):171-9, 2004.
53
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Neuroscience Nursing 30(4):245-52, 1998.
54
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Sherwood PR, Given BA, Given CW, Schiffman RF, Murman DL, Lovely M et al. Predictors
of distress in caregivers of persons with a primary malignant brain tumor. Research in Nursing
& Health 29(2):105-20, 2006.
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Neuro-Oncology. Journal of Psychosocial Oncology 1994; 12:101-122.
57
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relative reports of handicap, psychiatric symptoms and rehabilitation. Disability &
Rehabilitation 25(6):259-66, 2003.
58
McArdle JM, George WD, McArdle CS, Smith DC, Moodie AR, Hughson AV et al.
Psychological support for patients undergoing breast cancer surgery: a randomised study. BMJ
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Spouses Caring for Patients with Brain Tumors. Journal of Psychosocial Oncology 1996; 14:4356.
60
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62
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communication between parents and children about maternal breast cancer. BMJ
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63
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cognitive appraisals, and psychological distress in children of cancer patients. Health
Psychology 15(3):167-75, 1996.
64
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65
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24(21):3498-9, 2006.
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Neurology 249(8):955-60, 2002.
67
Devine EC, Westlake SK. The effects of psychoeducational care provided to adults with cancer:
meta-analysis of 116 studies. Oncol Nurs Forum 1995; 22(9):1369-1381.
68
Meyer TJ, Mark MM. Effects of psychosocial interventions with adult cancer patients: a metaanalysis of randomized experiments. Health Psychol 1995; 14(2):101-108.
69
Greer S, Moorey S, Baruch JD, Watson M, Robertson BM, Mason A et al. Adjuvant
psychological therapy for patients with cancer: a prospective randomised trial. BMJ 1992;
304(6828):675-680.
70
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cancer patients: results of two meta-analyses. Br J Cancer 1999; 80(11):1770-1780.
71
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neurooncology: a qualitative study of possibilities, limitations, and pitfalls. Palliative &
Supportive Care 3(2):121-30, 2005.
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in the follow-up of patients with malignant glioma. Clinical Oncology (Royal College of
Radiologists) 12(1):36-41, 2000.
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cerebral glioma : a systematic literature review. Supportive Care in Cancer 11(1):21-9, 2003.
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13
REHABILITATION
Brain tumour patients commonly experience changes in function and life quality during the course of
their disease. The most common deficits include impaired cognition (80% of patients), weakness
(78%), visual and perceptual deficit (53%), sensory loss (38%), and bowel and bladder dysfunction
(37%).1 While the traditional measures of clinical care tend to focus on direct tumour-related
outcomes (morbidity, survival time, histopathology, imaging and laboratory data, and side effects of
oncology treatments), rehabilitation therapies and outcome measurements offer a more functional
approach that focuses on the total impact of treatments on the patient’s life and social participation.
In general, patients with brain tumours (including gliomas) in the post-acute care stage respond to
rehabilitation therapies in much the same way as patients with other more �benign’ neurological
problems.
13.1
Description of rehabilitation environment
The standard rehabilitation care environment is multidisciplinary, with an appropriate range of
medical, nursing and allied health professionals available and supervision of patient care by a medical
specialist in rehabilitation medicine. Rehabilitation nurse specialists support patients and their carers
by integrating care programs with the application of skills learned in therapy sessions at other times,
in ward and other non-hospital settings.
Treatment roles of major individual therapy groups are defined, with areas of cooperative overlap.
Physiotherapists primarily focus on impairments of an individual’s motor function, strength and
coordination, and their balance and mobility. Occupational therapists focus on second order self-care:
the problems of function arising from patients’ impairments as they restrict the individual’s daily
personal and independent living activities, and assessment of both the individual and their care
environment. The main focus of speech pathologists is therapy for swallowing, communication and
verbal interaction, and memory problems, with appropriate support from psychologists and social
workers.
13.2
Common rehabilitation problems
Weakness was the second most common deficit reported in patients with brain tumours.1 Muscle
weakness may be related to an isolated limb weakness, hemiparesis, steroid-induced myopathy or
other neurological impairment, for example, ataxic hemiparesis.2 It may also be associated with
sensory loss, cranial nerve palsy, dysarthria, dysphagia, aphasia, ataxia, diplopia and general
debilitation. Symptoms will depend on the size, location and type of the brain tumour.3
Neurological impairment resulting in functional decline can affect bed mobility, ambulation,
transferring from sitting or lying to standing, and activities of daily living (dressing, bathing,
toileting). All these deficits can benefit from rehabilitation. The same principles of neurorehabilitation applied to persons with traumatic brain injury and stroke are appropriate for patients
with brain tumours. Given the likelihood of progressive decline, flexibility in approach and frequent
reassessments are required.4,5 Studies addressing early stages of brain tumours (and metastatic
tumours) have shown that brain tumour patients can achieve functional gains and rates of discharge
comparable to those of patients with stroke, and have a shorter hospital stay.6–8
The physiotherapist, occupational therapist, speech pathologist and dietician need to assess the
functional status of the patient to identify whether it would be safe to discharge the patient home. If
unsafe, the social worker could assist in finding alternative discharge options for the patient. It may be
advisable that the patient be assessed and educated regarding driving (see section 13.5.5). A combined
approach between all members of the multidisciplinary team is essential for good patient
management.
Rehabilitation
191
Recommendation
Level
References
Brain tumour patients should receive neuro-rehabilitation and
can achieve functional gains and rates of discharge
comparable to those of patients with stroke with a shorter
hospital stay.
III
5,7
The management of neurological muscle weakness includes range-of-motion exercises, strengthening
exercises, neuromuscular facilitation techniques and functional electrical stimulation. Specific aids
may be prescribed by the consultant in rehabilitation medicine, for example, an ankle foot orthosis to
improve gait.5 Modified devices for walking may be recommended, including wide-based quad-sticks,
standard walkers and hemi-walkers to increase the base of support and decrease the risk of falls.
A multidisciplinary approach is especially important in the management of hemi-spatial neglect,
where rehabilitation programs involving occupational therapists and physiotherapists should be
considered.5 Exercise for cardiovascular conditioning and resistance training enhances the strength
and endurance of preserved muscle groups. Cancer patients have the potential to improve from
rehabilitation, but the timing, intensity and pace of activity must be in accordance with patient’s goals
and status.9 Appropriate equipment such as mobility aids, commodes, dressing and bath devices are
prescribed by the occupational therapist and physiotherapist.10 Home modifications such as ramps and
rails provide additional safety and independence in the home. Family, and training and education, are
also important.
Cranial nerve damage may result in speech and swallowing dysfunction, optic neuropathy, ocular
muscle paresis, trigeminal neuropathy, facial weakness and/or hearing loss. Referral to a speech
pathologist will ensure training in techniques to prevent aspiration such as neck flexion, glottic
adduction exercises, turning the head towards the weak side, breath-holding during swallowing, the
selection of appropriate swallowing consistencies, and postural adjustments. Strategies to improve
quality of speech include pacing, proper breath support and over-articulation. A modified barium
swallow examination will assist in selecting the safest strategies for dysphagia.9,10
When managing ataxia secondary to cerebellar dysfunction, the application of weights to assistive
devices and/or extremities may improve stability for severely affected patients. Safety awareness and
measures to ensure an adequate base of support (eg walking aids) during motor activity are important
educational strategies. Strengthening unaffected motor groups with resistive exercises helps
compensate for impaired coordination.9,10
Compensatory techniques, the provision of assistive and orthotic devices, and exercise to enhance
patients’ preserved proprioception are recommended in the management of sensory dysfunction.
Occupational therapists will encourage patients to engage in fine motor skills required for self care.
Reliance on visual rather than tactile feedback is stressed. Unaffected motor groups are strengthened
with resistive exercises to help compensate for impaired coordination. Upper extremities must be
carefully positioned so as to reduce contractures, shoulder subluxation, pain and spasticity. Oedema
management will help prevent chronic pain and assist in motor recovery. The use of elevation and/or
washable spandex gloves or coban wraps, and compression stockings and massage is
recommended.9,10
Steroid-induced myopathy is characterised clinically by proximal muscle weakness and eventual
muscle wasting, especially in the pelvic girdle. One of the most frequent complaints is an inability to
arise from the seated position. The myopathy can progress to involve the arms and neck. Evaluation
of neck and hip flexor strength is required.11,12 Respiratory muscles may also be affected, resulting in
symptomatic dyspnoea.13 Treatment is dependent on the reduction or discontinuation of steroids (if
possible) plus physiotherapy, occupational therapy and a high-protein diet.13
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
13.3
Rehabilitation outcome measurements
Two measures of rehabilitation outcomes are commonly used. The older and simpler scale is the
Barthel Index14, which focuses on personal activities of daily living and basic mobility functions.
Items are added to produce a score between 0 and 100; better scores show increased independence.
Excellent internal consistency has been shown15, with good inter-rater and test-retest reliability.16
The current standard scale for rehabilitation outcomes assessment is the FIMTM (Functional
Independence Measure17), which is an 18-item instrument, each item being rated from 1 (complete
dependence) to 7 (independence). The items are grouped to evaluate various aspects of motor function
(transfers, walking, stairs, bowel and bladder control), activities of daily living (ADL) function
(eating, grooming, bathing, dressing, toileting), and cognitive-communication function (speech
communication, social interaction, problem-solving, memory). Full-scale scores thus range from 18 to
126. The three functional groupings approximately correspond to various areas of therapy, as
described above. The scale has excellent internal consistency18, and excellent inter-rater and test–
retest reliability.19
13.4
Rehabilitation outcomes for brain tumour patients
Review of the literature found no randomised control trials of outcomes of rehabilitation therapy for
disability in individuals with diagnosis of glioma, or of brain tumours more generally.
Seven observational studies1,7,20–24 describe the rehabilitation of individuals having disability
associated with brain tumours, including gliomas. Four studies1,20-22 are non-comparative, and
three7,23,24 compare outcomes of therapy in brain tumour patients with brain trauma or stroke patients.
All seven studies show improvement in patients’ functional status during the course of rehabilitation
therapy, using the FIMTM.
Of the four non-comparative studies, only Marciniak et al20 analysed the relationship of tumour
histology with outcomes of rehabilitation, and they separately group and compare Grade III and IV
astrocytomas with other tumour categories (meningiomas, brain secondaries, other brain
malignancies). They found no difference in average length of stay or change in functional outcome
between primary brain tumours and other tumour categories.
Mukand et al1 describe therapy program results for patients with brain tumours, employing the FIMTM
as a single domain. Three other studies divide the FIMTM into two domains: a motor function ADL
domain and a cognitive-communication domain.20–22 In addition, Garrard et al22 separately measure
ADL function using the Barthel score.
Three studies using the FIMTM describe similar improvements in functional status in patients with
brain tumours, in comparison with rehabilitation outcomes for brain trauma patients7,23 and for stroke
patient.24
While there is no evidence relating neuropsychological intervention to functional outcomes in brain
tumour patients, cognitive impairment related either to disease or treatment will clearly affect ability
to participate in rehabilitation programs, as well as quality of life. Observational studies describe the
place of formal assessment of cognitive impairment after treatment of brain tumours.25–27
There are two comprehensive reviews6,28 of rehabilitation therapy in individuals with brain tumours
that suggest that rehabilitation should be offered to patients with glioma.
Return to driving a motor vehicle after treatment for brain tumour is covered by national guidelines
with regulatory force, in all Australian jurisdictions (see 13.5.5 below).29
Rehabilitation
193
13.5
Recovery outcomes of therapy for specific problems in
patients with brain tumours
13.5.1
Association of rehabilitation therapy with improved motor/mobility
function in patients with brain tumours
There is level III evidence that participation in a rehabilitation program is associated with improved
performance of mobility function in patients with brain tumours21,22 and at a rate comparable to
improvement seen with rehabilitation therapy of motor function in benign neurological
diagnoses.6,23,24 While the gains in motor function are slightly less for high-grade gliomas, these
patients nevertheless improve with therapy, and with an improvement rate similar to other brain
tumour groups.20
Specific physiotherapy interventions which promote recovery of hemiplegic lower limb function are
described in a case series which includes two brain tumour patients.30
13.5.2
Association of rehabilitation therapy with improved daily living
functional ability in patients with brain tumours
There is level III evidence that participation in a rehabilitation program is associated with improved
performance of personal activities of daily living, in patients with brain tumours.22
13.5.3
Association of rehabilitation therapy with improved cognitivecommunication function and swallowing function in patients with brain
tumours
There is level III evidence that participation in a rehabilitation program is associated with
improvement in cognitive-communication function in patients with high-grade gliomas,20 with an
efficiency rate similar to other brain tumour groups.
There is no evidence for the use of speech therapy in managing swallowing disorders due to brain
tumours but speech therapy may assist with residual problems related to swallowing, communication
and cognitive function.
13.5.4
Association of neuropsychological intervention with improved
outcomes in patients with brain tumours
There is no evidence relating neuropsychological interventions to outcomes in therapy programs for
brain tumour patients. Observational evidence does however support neuropsychological evaluation
of cognitive impairment after treatment of brain tumours.26,27,31
13.5.5
Criteria to indicate a possible safe return to driving after brain tumour
treatment
National guidelines have been published,29 with regulatory force in all Australian jurisdictions.
If a person has evidence of residual malignant brain tumour, or persisting hemianopia, quadrantanopia
or diplopia, or uncontrolled epilepsy or impaired judgement after treatment of a brain tumour, they do
not satisfy the criteria relevant to a diagnosis of glioma, for holding any commercial driver’s licence,
or an unrestricted private driver’s licence.
Formal functional assessment, by a rehabilitation service, of the balance between demonstrated
residual disability and the skills necessary to drive a motor vehicle is the best way to manage potential
risks associated with brain tumour patients who expect to return to driving a car as part of their
normal daily activities. This may involve medical, ophthalmological, psychological and occupational
therapy assessments. It may occur in both off-road and on-road settings.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
This will lead to determination: that the person is not safe to drive at all; or is safe to drive with some
restrictions; or is safe to drive an adapted vehicle; or may drive without restriction. Recommendations
are then made to the relevant driver licensing authority for its determination and appropriate
endorsement of the person’s driving licence. It is incumbent on the person to obey the determination
of the driver licensing authority.
Recommendation
Level
References
Patients having residual problems after treatment of a glioma,
with stable medical status, should be referred to a rehabilitation
service with a range of medical, nursing and allied health
professionals for multidisciplinary assessment and appropriate
therapy and support of their problems, involving both the patient
and their carers.
III
7–11,18
Physiotherapy should be offered to those glioma patients with
residual problems in motor function, strength, and coordination,
or balance and gait problems.
III
9,10,20
Occupational therapy should be offered to those glioma
patients with residual problems in personal care and
independent activities of daily living. As well as treating individual
needs, therapy should also address the person’s social and
physical environment of care, and be supported by social worker
intervention.
III
10
Therapy by a speech pathologist should be offered to those
glioma patients with residual problems related to swallowing,
communication and cognitive function. Where the services are
available, this should be supported by assessment and
intervention by a clinical psychologist or a neuropsychologist.
III
7
Glioma patients expecting to return to driving after treatment of
their tumour should be referred to a rehabilitation service for full
assessment of their ability to drive safely. Any resulting
determinations of the driver licensing authority must be observed.
For those who can return to driving, regular ongoing follow-up by
the rehabilitation service is indicated, to review and manage any
continuing risk associated with driving. Those who continue to
drive unsafely, contrary to advice and the determinations of the
driver licensing authority, should be counselled about the need
to behave responsibly and the advice of the authority be sought,
if they still continue to drive. In some situations, cancellation of
the driver’s licence may be necessary.
I
19
References
1
Mukand JA, Blackinton DD, Crincoli MG, Lee JJ, Santos BB. Incidence of neurologic
deficits and rehabilitation of patients with brain tumors. American Journal of Physical
Medicine & Rehabilitation 80(5):346–50, 2001.
2
Davies E, Hall S, Clarke C. Two year survival after malignant cerebral glioma: patient and
relative reports of handicap, psychiatric symptoms and rehabilitation. Disability &
Rehabilitation 25(6):259–66, 2003.
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3
Snyder H, Robinson K, Shah D, Brennan R, Handrigan M. Signs and symptoms of patients
with brain tumors presenting to the emergency department. Journal of Emergency Medicine
11(3):253–8, 1993;-Jun.
4
Guo Y, Shin KY. Rehabilitation Needs of Cancer Patients. Critical Reviews in Physical and
Rehabilitative Medicine 2005; 17(2):83–99.
5
Kirshblum S, O'Dell MW, Ho C, Barr K. Rehabilitation of persons with central nervous
system tumors. Cancer 92(4 Suppl):1029–38, 2001.
6
Huang ME, Wartella J, Kreutzer J, Broaddus W, Lyckholm L. Functional outcomes and
quality of life in patients with brain tumours: a review of the literature. Brain Injury
15(10):843–56, 2001.
7
Huang ME, Cifu DX, Keyser-Marcus L. Functional outcomes in patients with brain tumor
after inpatient rehabilitation: comparison with traumatic brain injury. American Journal of
Physical Medicine & Rehabilitation 79(4):327–35, 2000;-Aug.
8
Sherer M, Meyers CA, Bergloff P. Efficacy of postacute brain injury rehabilitation for
patients with primary malignant brain tumors. Cancer 80(2):250–7, 1997.
9
Cheville A. Rehabilitation of patients with advanced cancer. Cancer 92(4 Suppl):1039–48,
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Mukand JA, Guilmette TJ, Tran M. Rehabilitation for Patients with Brain Tumors. Critical
Reviews in Physical and Rehabilitative Medicine 2005; 15(2):99–111.
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Batchelor TT, Byrne TN. Supportive care of brain tumor patients. Hematology–Oncology
Clinics of North America 2006; 20(6):1337–1361.
12
Batchelor TT, Taylor LP, Thaler HT, Posner JB, DeAngelis LM. Steroid myopathy in cancer
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13
Gallagher CG. Respiratory steroid myopathy. American Journal of Respiratory & Critical
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14
Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965;
14:61–65.
15
Shah S, Vanclay F, Cooper B. Improving the sensitivity of the Barthel Index for stroke
rehabilitation. J Clin Epidemiol 1989; 42(8):703–709.
16
Loewen SC, Anderson BA. Reliability of the Modified Motor Assessment Scale and the
Barthel Index. Phys Ther 1988; 68(7):1077–1081.
17
Keith RA, Granger CV, Hamilton BB, Sherwin FS. The functional independence measure: a
new tool for rehabilitation. Adv Clin Rehabil 1987; 1:6–18.
18
Dodds TA, Martin DP, Stolov WC, Deyo RA. A validation of the functional independence
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19
Ottenbacher KJ, Mann WC, Granger CV, Tomita M, Hurren D, Charvat B. Inter-rater
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Med Rehabil 1994; 75(12):1297–1301.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
20
Marciniak CM, Sliwa JA, Heinemann AW, Semik PE. Functional outcomes of persons with
brain tumors after inpatient rehabilitation. Archives of Physical Medicine & Rehabilitation
82(4):457–63, 2001.
21
Cole RP, Scialla SJ, Bednarz L. Functional recovery in cancer rehabilitation. Archives of
Physical Medicine & Rehabilitation 81(5):623–7, 2000.
22
Garrard P, Farnham C, Thompson AJ, Playford ED. Rehabilitation of the cancer patient:
experience in a neurological unit. Neurorehabilitation & Neural Repair 18(2):76–9, 2004.
23
O'Dell MW, Barr K, Spanier D, Warnick RE. Functional outcome of inpatient rehabilitation
in persons with brain tumors. Archives of Physical Medicine & Rehabilitation 79(12):1530–4,
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24
Huang ME, Cifu DX, Keyser-Marcus L. Functional outcome after brain tumor and acute
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25
Brown PD, Buckner JC, Uhm JH, Shaw EG. The neurocognitive effects of radiation in adult
low-grade glioma patients. Neuro-Oncology 5(3):161–7, 2003.
26
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27
Costello A, Shallice T, Gullan R, Beaney R. The early effects of radiotherapy on intellectual
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29
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14
FOLLOW-UP
14.1
General approach
The aim of follow-up for patients with either low- or high-grade astrocytoma is to evaluate tumour
control, monitor and manage symptoms from tumour and treatment, and provide psychological
support for the patient and their family.
The optimal frequency of follow-up visits is unknown and should be determined by the patient’s
clinical condition. However, a routine follow-up schedule of one to three monthly check-ups for
patients with high-grade astrocytoma and three to six monthly visits for patients with low-grade
astrocytoma would appear reasonable. The exact schedule will vary according to the patient’s
condition.
It is suggested that follow-up be undertaken in a setting where the patient has access to members of
the multi-disciplinary team involved in their care. The team should include the treating specialists,
neurologists, social workers, nurses, radiologists, physiotherapy, occupational therapy rehabilitation
and palliative care specialists. A point of contact should be explicit. The lead physician may change
over time depending on the patient’s therapeutic needs. The general practitioner (GP) will also be
involved in patient care but because gliomas are uncommon the GP’s experience of gliomas will be
limited and they are usually reluctant to be involved in tumour-specific follow-up.
While there are no high-level data that examine the benefits of care coordination, care coordination
has become routine for most tumour sites. Brain tumour patients have a complex and difficult clinical
course that involves multiple specialist clinical groups and repeated investigations. Care coordination
is likely to significantly reduce the burden on patients and their carers.
There are many issues that need consideration during the follow-up of glioma patients including
dexamethasone and anticonvulsant dosage, rehabilitation, driving, imaging frequency, palliative and
pastoral care. They are discussed briefly below because other chapters in these guidelines provide
detailed information.
Dexamethasone dose should be gradually reduced and ceased when possible. Dexamethasone should
not be ceased suddenly because severe and sometimes catastrophic cerebral oedema can result. It may
mimic tumour progression clinically and radiologically but can be rapidly reversed by the
reintroduction of dexamethasone. Dose reduction should be titrated to patient symptoms. It may take
up to one week for a reduction in dexamethasone dose to result in cerebral oedema so the titration
must be undertaken slowly. Patients should be monitored for symptoms of the common side effects of
dexamethasone such as high blood sugar, osteoporosis, proximal myopathy and gastric erosions (see
Chapter 11 Symptom management and complications).
Anticonvulsants should only be ceased after consultation with a neurologist. Patients should have a
prolonged period without a seizure, stable disease and a normal EEG. Medications should be slowly
withdrawn over a period of months (see Chapter 11 Symptom management and complications).
Patients with brain tumours are only legally allowed to drive if they have no evidence of active
tumour and are seizure free. This is unusual in patients with grade IV gliomas. Cognitive changes that
are not readily apparent in a clinical consultation may severely impede safe driving. It is
recommended that all patients are assessed by a rehabilitation physician and occupational therapist
before being certified as safe to drive (see Chapter 13 Rehabilitation).
Follow-up imaging and interpretation is discussed in the next section. (For palliative and pastoral care
see Chapter 15 Palliative care).
198
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Key points:
•
The aim of follow-up for patients is to evaluate tumour control, monitor and manage
symptoms from tumour and treatment, and provide psychological support.
•
The optimal frequency of follow-up visits is unknown and should be determined by the
patient’s clinical condition.
•
Follow-up should be undertaken in a setting where the patient has access to members of
the multi-disciplinary team.
•
Dexamethasone dose should be gradually reduced and ceased when possible.
14.2
High-grade gliomas—imaging after surgery
14.2.1
Modalities to define tumour recurrence
Gadolinium enhanced MRI
Gadolinium enhanced MRI (Gd-MRI) is the imaging standard of reference for all intracranial
neoplasms and is hence the preferred modality of choice except in the presence of contraindications
such as a pacemaker.
There are no current standardised guidelines for either the timing or frequency of post-treatment
imaging studies. The pre-operative study should have sufficient sequence variety to enable
comparison and determination of interval change with the initial post-operative study, such as changes
related to the surgery, like infarction. For example, the pre-operative imaging should include a T1weighted sequence (pre and post contrast) and a T2-weighted sequence (preferably FLAIR – fluid
attenuated inversion recovery).
Post-operative pre-contrast and post-contrast images should be obtained within 24 hours of surgery.
These are best obtained with the same slice placement orientation as the pre-operative study and
should also contain FLAIR, T1 pre and post contrast and diffusion-weighted imaging (to detect
surgery-related infarction). This early study may determine the extent of resection with minimal
confounding factor influence.
Follow-up surveillance MRI frequency thereafter will be influenced by extent of residual disease,
different adjunctive therapy regimens, clinical trial enrolment, onset of new symptoms, patient
compliance, and health status. Serial imaging at two to three month intervals is often used.
The definition of tumour progression on Gd-MRI has not been standardised and has been variously
suggested as a 25% increase in the cross-sectional area of the tumour in the slice with the greatest
amount of tumour, or as a 25% increase in contrast-enhancing volume. Recurrence has also been
defined as a greater-than 50% growth in the time between two successive imaging studies.
Progression may, however, occur at some distance from the original resection site in up to 10% of
patients.1,2 It may be difficult to determine progression because of �pseudo-progression’, which may
be seen in up to 50% of cases after radiotherapy and chemotherapy.
Magnetic resonance spectroscopy
Magnetic resonance spectroscopy (MRS) is becoming more readily available and is useful in the
follow-up of high-grade gliomas that have undergone radiation therapy when radiation necrosis is a
significant possibility. Multi-voxel technique is strongly preferred because it gives a more
representative sample. MRS is able to more accurately distinguish between tumour recurrence and
radiation necrosis (which are essentially indistinguishable on conventional MRI). MRS of tumour
recurrence demonstrates elevated choline/NAA and choline/creatinine ratios with choline to
Follow-up
199
contralateral choline ratios >1, although the precise cut-off values used in the literature have varied.
Lactate peaks may indicate necrosis. Areas of mixed necrosis and neoplasm are however not
uncommon and in these regions the spectral patterns are often less definitive. Thus, MR spectroscopy
limitations exist and other non-invasive techniques (see below) may be employed.3–28
Perfusion MR
Perfusion MR (pMRI) or dynamic susceptibility contrast-enhanced MR may also be obtained in the
same imaging sitting as Gd-MRI and MRS. pMRI has been shown to enable earlier distinction of
responders to therapy than conventional MRI. In addition, it may be used to distinguish radiation
necrosis and tumour recurrence, with tumour recurrence typically having an elevated relative CBV
(cerebral blood volume), although once again methods of calculation and cut-off values vary in the
literature7,14,15,29–36
Permeability MR
Permeability MR is not generally clinically available at present and hence does not have a significant
role.
Diffusion-weighted imaging
Diffusion-weighted imaging with estimation of apparent diffusion coefficients (ADC) has
demonstrated promise in improving the distinction of radiation necrosis and tumour recurrence and
currently plays an adjunct role to Gd-MRI, MRS and pMRI. Tumour recurrence generally displays
reduced diffusion due to cellularity. Diffusion tensor imaging (DTI) is a relatively new technique that
in early studies has also demonstrated promise in this distinction.24,25,37–47
Positron emission tomography
Flurodeoxy-glucose (FDG)-positron emission tomography (PET) remains a useful tool in the followup of high-grade gliomas, however its use is largely confined to attempting to distinguish between
radiation necrosis and tumour recurrence when other MR methods have proven inconclusive. Other
PET tracers are largely experimental. In the event that Gd-MRI is not conclusive for recurrence, FDGPET may be considered an appropriate �problem-solving’ evaluation.2,15,48–99
Single photon emission computed tomography
Single photon emission computed tomography (SPECT) is more readily available than PET and much
cheaper. Of the radionuclides used, Thallium-201 and Technecium-99m Sestamibi are probably the
most successful and most readily available SPECT tracers used for the differentiation of radiation
necrosis and tumour recurrence. These tracers have a relatively high specificity, lower cost but poorer
spatial resolution compared to PET.40,44,62,63,66,67,75–77,83,87,94,100–111
A comprehensive imaging practice might routinely include Gadolinium enhanced MRI, MRS,
perfusion MR and diffusion-weighted imaging. The interpretation is based around FIVE parameters
including: extent of T2 hyperintensity (best appreciated on FLAIR), contrast-enhancing volume,
lesion ADC, lesion rCBV and spectral data.
The radiological changes of glioma progression include:
200
•
increased extent of T2 signal abnormality
•
increased enhancing volume
•
elevated rCBV (eg approximately cortex or higher and increasing on serial studies)
•
elevated choline/creatinine (eg >2), elevated choline to NAA and choline to contralateral
normal >1 with an increase in these values on serial studies, and/or low ADC.
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
For a diagnosis of recurrent high-grade glioma there should be concordance of three or more of the
above radiological changes.
14.3
Low-grade gliomas—imaging after surgery
14.3.1
Modalities to define tumour recurrence
MRI gadolinium enhanced
MRI gadolinium enhanced (Gd-MRI) is the imaging standard of reference for all intracranial
neoplasms and is hence the preferred modality of choice except in the presence of contraindications
such as a pacemaker.
There are no current standardised guidelines for either the timing or frequency of post-treatment
imaging studies. The pre-operative study should have sufficient sequence variety to enable
comparison and determination of interval change with the initial post-operative study (ie change
related to the surgery, such as infarction). For example, the pre-operative imaging should include a
T1-weighted sequence (pre and post contrast) and a T2-weighted sequence (preferably FLAIR).
Post-operative pre-contrast and post-contrast images should be obtained within 24 hours of surgery.
These are best obtained with the same slice placement orientation as the pre-operative study and
should also contain FLAIR, T1 pre- and post-contrast and diffusion-weighted imaging (to detect
surgery-related infarction). This early study may determine the extent of resection with minimal
confounding factor influence.
Follow-up surveillance MRI frequency thereafter will be influenced by the extent of residual disease,
different adjunctive therapy regimens, clinical trial enrolment, onset of new symptoms, patient
compliance, and health status. Serial imaging at three-month intervals initially is often used and the
time interval generally gradually increased if there is no detectable change on serial imaging
investigations.
The definition of tumour progression in LGG has not been standardised. MRI changes that indicate
progression include increase in size and the presence of new lesions. The development of contrast
enhancement or necrosis may indicate transformation to higher-grade glioma. Changes in the amount
of T2 signal may be due to tumour progression or to post-treatment oedema.
Other MRI modalities
MRS is becoming more readily available and may be useful in the follow-up of low-grade gliomas
that have undergone radiation therapy such that radiation necrosis is a significant possibility.
Perfusion MRI has recently been shown to correlate with outcome in LGGs and hence may be a
useful adjunct to the follow-up of these lesions.112–114 Permeability MR is not generally available.
ADC map evaluation and diffusion tensor imaging (DTI) do not appear to have particular practical
value in the follow-up of LGGs at present.42
Nuclear medicine imaging
PET evaluation in the follow-up imaging of LGGs has not developed into a clinical tool at present.115–
118
SPECT evaluation in the follow-up of LGGs has not developed into a useful clinical tool at
present.118
14.3.2
Interpretation criteria—low-grade transformation to higher-grade
Progression is expected to show:
•
increased extent of T2 signal abnormality
•
increased enhancing volume or development thereof
Follow-up
201
•
elevated rCBV (eg approximately cortex or higher and increasing on serial studies)
•
elevated choline/creatinine (eg >2), elevated choline to NAA and choline to contralateral
normal >1, with increase in these values on serial studies.
It should be noted that oligodendrogliomas may demonstrate high-grade features on multiple
parameters such as perfusion, spectroscopy, but may not be high grade.
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and grading of recurrences in patients pretreated for gliomas at follow-up: a comparative
study with stereotactic biopsy. Eur J Nucl Med 1999; 26(2):144–151.
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Stokkel M, Stevens H, Taphoorn M, Van Rijk P. Differentiation between recurrent brain
tumour and post-radiation necrosis: the value of 201Tl SPET versus 18F-FDG PET using a
dual-headed coincidence camera--a pilot study. Nucl Med Commun 1999; 20(5):411–417.
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Thompson TP, Lunsford LD, Kondziolka D. Distinguishing recurrent tumor and radiation
necrosis with positron emission tomography versus stereotactic biopsy. Stereotact Funct
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79
Berman CG, Clark RA. Positron emission tomography in initial staging and diagnosis of
persistent or recurrent disease. Curr Opin Oncol 2000; 12(2):132–137.
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Brock CS, Young H, O'Reilly SM, Matthews J, Osman S, Evans H et al. Early evaluation of
tumour metabolic response using [18F]fluorodeoxyglucose and positron emission
tomography: a pilot study following the phase II chemotherapy schedule for temozolomide in
recurrent high-grade gliomas. Br J Cancer 2000; 82(3):608–615.
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Langleben DD, Segall GM. PET in differentiation of recurrent brain tumor from radiation
injury. J Nucl Med 2000; 41(11):1861–1867.
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Chao ST, Suh JH, Raja S, Lee SY, Barnett G. The sensitivity and specificity of FDG PET in
distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic
radiosurgery. Int J Cancer 2001; 96(3):191–197.
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Iwai Y, Yamanaka K, Oda J, Tsuyuguchi N, Ochi H. Tracer accumulation in radiation
necrosis of the brain after thallium-201 SPECT and [11C]methionine PET--case report.
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Mirzaei S, Knoll P, Kohn H. Diagnosis of recurrent astrocytoma with fludeoxyglucose F18
PET scanning. N Engl J Med 2001; 344(26):2030–2031.
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Bingham JB. Where can FDG-PET contribute most to anatomical imaging problems? Br J
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Wong TZ, van der Westhuizen GJ, Coleman RE. Positron emission tomography imaging of
brain tumors. Neuroimaging Clin N Am 2002; 12(4):615–626.
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Benard F, Romsa J, Hustinx R. Imaging gliomas with positron emission tomography and
single-photon emission computed tomography. Semin Nucl Med 2003; 33(2):148–162.
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Spence AM, Mankoff DA, Muzi M. Positron emission tomography imaging of brain tumors.
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Spaeth N, Wyss MT, Weber B, Scheidegger S, Lutz A, Verwey J et al. Uptake of 18Ffluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in
the rat: implications for separation of radiation necrosis from tumor recurrence. J Nucl Med
2004; 45(11):1931–1938.
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Tsuyuguchi N, Takami T, Sunada I, Iwai Y, Yamanaka K, Tanaka K et al. Methionine
positron emission tomography for differentiation of recurrent brain tumor and radiation
necrosis after stereotactic radiosurgery--in malignant glioma. Ann Nucl Med 2004;
18(4):291–296.
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Hustinx R, Pourdehnad M, Kaschten B, Alavi A. PET imaging for differentiating recurrent
brain tumor from radiation necrosis. Radiol Clin North Am 2005; 43(1):35–47.
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Popperl G, Goldbrunner R, Gildehaus FJ, Kreth FW, Tanner P, Holtmannspotter M et al. O(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of convection-enhanced
delivery of paclitaxel in patients with recurrent glioblastoma. Eur J Nucl Med Mol Imaging
2005; 32(9):1018–1025.
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Rachinger W, Goetz C, Popperl G, Gildehaus FJ, Kreth FW, Holtmannspotter M et al.
Positron emission tomography with O-(2-[18F]fluoroethyl)-l-tyrosine versus magnetic
resonance imaging in the diagnosis of recurrent gliomas. Neurosurgery 2005; 57(3):505–511.
94
Siepmann DB, Siegel A, Lewis PJ. Tl-201 SPECT and F-18 FDG PET for assessment of
glioma recurrence versus radiation necrosis. Clin Nucl Med 2005; 30(3):199–200.
95
Van Laere K, Ceyssens S, Van Calenbergh F, de Groot T, Menten J, Flamen P et al. Direct
comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma:
sensitivity, inter-observer variability and prognostic value. Eur J Nucl Med Mol Imaging
2005; 32(1):39–51.
96
Charnley N, West CM, Barnett CM, Brock C, Bydder GM, Glaser M et al. Early change in
glucose metabolic rate measured using FDG-PET in patients with high-grade glioma predicts
response to temozolomide but not temozolomide plus radiotherapy. Int J Radiat Oncol Biol
Phys 2006; 66(2):331–338.
97
Popperl G, Kreth FW, Herms J, Koch W, Mehrkens JH, Gildehaus FJ et al. Analysis of 18FFET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to
standard methods? J Nucl Med 2006; 47(3):393–403.
98
Wang SX, Boethius J, Ericson K. FDG-PET on irradiated brain tumor: ten years' summary.
Acta Radiol 2006; 47(1):85–90.
99
Xiangsong Z, Changhong L, Weian C, Dong Z. PET Imaging of cerebral astrocytoma with
13N-ammonia. Journal of Neuro-Oncology 78(2):145–51, 2006.
100
Barai S, Bandopadhayaya GP, Julka PK, Malhotra A, Bal CS, Dhanpathi H. Imaging using
Tc99m-tetrofosmin for the detection of the recurrence of brain tumour: a comparative study
with Tc99m-glucoheptonate. J Postgrad Med 2004; 50(2):89–93.
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Beauchesne P, Soler C, Maatougui K, Schmitt T, Barral FG, Michel D et al. [Is cerebral
tomoscintigraphy with 99mTc-MIBI useful in the diagnosis of local recurrence in patients
with malignant gliomas?]. Cancer Radiother 1998; 2(1):42–48.
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Carvalho PA, Schwartz RB, Alexander E, III, Garada BM, Zimmerman RE, Loeffler JS et al.
Detection of recurrent gliomas with quantitative thallium-201/technetium-99m HMPAO
single-photon emission computerized tomography. J Neurosurg 1992; 77(4):565–570.
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thallium-201 SPECT imaging in childhood brain tumors. Pediatr Neurosurg 1994; 20(1):11–
18.
104
Mullan BP, O'Connor MK, Hung JC. Single photon emission computed tomography brain
imaging. Neurosurg Clin N Am 1996; 7(4):617–651.
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Schillaci O, Spanu A, Madeddu G. [99mTc]sestamibi and [99mTc]tetrofosmin in oncology:
SPET and fusion imaging in lung cancer, malignant lymphomas and brain tumors. Q J Nucl
Med Mol Imaging 2005; 49(2):133–144.
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Schwartz RB, Carvalho PA, Alexander E, III, Loeffler JS, Folkerth R, Holman BL. Radiation
necrosis vs high-grade recurrent glioma: differentiation by using dual-isotope SPECT with
201TI and 99mTc-HMPAO. AJNR Am J Neuroradiol 1991; 12(6):1187–1192.
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Soler C, Beauchesne P, Maatougui K, Schmitt T, Barral FG, Michel D et al. Technetium-99m
sestamibi brain single-photon emission tomography for detection of recurrent gliomas after
radiation therapy. Eur J Nucl Med 1998; 25(12):1649–1657.
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evaluation of recurrent brain tumor. Clin Nucl Med 1992; 17(8):663–664.
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tomography/computed tomography in brain tumors. Semin Nucl Med 2007; 37(1):34–47.
111
Gorska-Chrzastek M, Grzelak P, Bienkiewicz M, Tybor K, Zakrzewska E, Mikolajczak R et
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2001; 51(2):478–482.
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susceptibility-weighted contrast-enhanced perfusion MR imaging--prediction of patient
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emission tomography evaluation of slowly progressive gliomas. Eur J Cancer 1996;
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209
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Nuutinen J, Sonninen P, Lehikoinen P, Sutinen E, Valavaara R, Eronen E et al. Radiotherapy
treatment planning and long-term follow-up with [(11)C]methionine PET in patients with
low-grade astrocytoma. Int J Radiat Oncol Biol Phys 2000; 48(1):43–52.
118
Henze M, Mohammed A, Schlemmer H, Herfarth KK, Mier W, Eisenhut M et al. Detection
of tumour progression in the follow-up of irradiated low-grade astrocytomas: comparison of
3-[123I]iodo-alpha-methyl- L-tyrosine and 99mTc-MIBI SPET. Eur J Nucl Med Mol Imaging
2002; 29(11):1455–1461.
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15
PALLIATIVE CARE
Despite recent advances in diagnosis and treatment, primary brain tumours remain incurable for the
majority of patients. These patients have significant symptoms and concerns, posing considerable
burdens on relatives, carers and health professionals. Given the relatively short life expectancy of
these patients and the extent of their neurological debility, palliative care may be a significant
component of management.
15.1
General
This section has been modified from the Australian Cancer Network Clinical Practice Guidelines for
the Prevention, Diagnosis and Management of Lung Cancer1 according to the needs of brain tumour
patients.
Palliative care has been defined as coordinated medical, nursing and allied services for people with
life-limiting disease, delivered where possible in the environment of the person’s choice, and which
provides physical, psychological, emotional and spiritual support for patients and for patients’
families and friends. The provision of hospice and palliative care services includes grief and
bereavement support for the family and other carers during the life of the patient and continuing after
death.2 A palliative approach involving attention to symptom control and the psychological, social and
spiritual wellbeing of the patient and their family is relevant at all stages of the disease, and especially
in the terminal phase. Although focussing on quality of life, palliative care is also concerned with the
quality of dying.
Palliative care utilises advance planning rather than crisis intervention. It offers a multidisciplinary
model of care that is focused on the whole person within their social and emotional context, rather
than just the disease. However, a good knowledge of the natural history of the disease and relevant
oncological practice is essential for good quality palliative care.3
The Palliative Care Australia Standards for providing quality palliative care in any setting are listed in
Table 15.1.
Palliative care
211
Table 15.1
National Standards for the provision of quality palliative care (abridged)4
Care, decision-making and care planning are based on a respect for the uniqueness of the
patient, their caregiver and family.
The holistic needs of the patient, their caregiver, and family are acknowledged in the
assessment and care planning processes and strategies are developed to address those needs.
Ongoing and comprehensive assessment and care planning are undertaken to meet the needs
of the patient, their caregiver and family.
Care is coordinated to minimise the burden on patient, their caregiver/s and family.
The primary caregiver is provided with information, support and guidance about their role
according to their needs and wishes.
The unique needs of the dying patients are considered, their comfort maximised and their
dignity preserved.
The service has an appropriate philosophy, values, culture, structure and environment for the
provision of competent and compassionate palliative care.
The patient, their caregivers and family have access to bereavement care, information and
support services.
Community capacity to respond to the needs of people who have a life-limiting illness is built
through effective collaboration and partnerships.
Access to palliative care is available for all people based on clinical need and is independent
of diagnosis, age, cultural background or geography.
The service is committed to quality improvement and research in clinical and management
practices.
Staff and volunteers are appropriately qualified for the level of service offered and
demonstrate ongoing participation in continuing professional development.
Staff and volunteers reflect on practice and initiate and maintain effective self-care strategies.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
15.2
Specialist versus generalist palliative care
The National Strategy for Palliative Care encourages the use of existing networks and community
services in conjunction with palliative care specialists to deliver palliative care.5 All clinicians have a
responsibility to be proficient in basic palliative care. Most palliative care will be provided by the
existing network of carers, coordinated by either the general practitioner or treating physician or
oncologist. Referral to palliative care should not be limited to the end-of-life phase of illness. Difficult
cases will benefit from referral to a specialist palliative care service. In metropolitan areas, specialist
palliative care services are generally available both in hospital and in the community to provide expert
symptom management and supportive care. This may be a consultative service or involve transfer of
care to a palliative care physician. Access to specialist palliative care beds within hospitals or hospice
units is usually available. Access is more limited in rural and remote areas. Consultations may be by
telephone or video-conferencing and access to specialist inpatient care may be limited by distance. An
evolving role is that of a specialist neuro-oncology nurse to provide support for patients newly
diagnosed with a brain tumour as well as those with advanced disease.
As the availability of specialist palliative care increases, specialist palliative care teams should be
utilised to achieve optimum outcomes for the patient with brain tumours, particularly when treating
complex or difficult issues. The involvement of a specialist palliative care team in the care of patients
with cancer in general increases patient and carer satisfaction, increases the amount of time spent at
home by patients, reduces the time spent in hospital, reduces the overall cost of care and increases the
likelihood of the patient dying where they wish.6,7
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Recommendation
Level
References
Specialist palliative care services can improve outcomes in the
care of patients with cancer and should be available for all
appropriate patients.
I
6,7,8
Key point:
• Referral to palliative care should not be limited to the end-of-life phase of illness.
15.3
Sites of palliative care
Palliative care emphasises that care is delivered where possible in the environment of the patient and
carer’s choice.9 Good communication between health professionals is essential to ensure smooth
transition from one site to another. It is important to be clear which health professional bears the
primary responsibility for care in each setting. Continuity of care can be provided through clear
communication between all health care providers and the patient and family so that accurate and
detailed information about all aspects of the patient’s condition, treatment and wishes is known.
15.3.1
Own residence
This refers to either the patient’s own home, the home of another, a nursing home or hostel.
Increasingly, staff in nursing homes and hostels are being called on to deliver palliative care where
resources to care for a dying resident may be limited.10,11
The general practitioner will be the key medical practitioner in delivering palliative care at home,
usually with the assistance of community nurses. The local palliative care service will usually be able
to add the support of specialist palliative care nurses and a specialist palliative care physician as well
as counsellors, pastoral care workers and volunteers. Links with other community services mean that
assistance can be accessed for physiotherapy, nutritional support, occupational therapy and home
help.4
If unnecessary hospital admissions are to be avoided, it is essential that the patient and family know
who to call in the event of a crisis and have access to support 24 hours a day, seven days a week. The
latter is not achievable in many areas. Although reliable data are limited, home-care programs that
provide adequate support for the carers are generally assessed favourably.12–15 Carers and relatives of
terminally ill patients report more support was needed during care at home, particularly for activities
of daily living and domestic chores.16 Families undertaking home care experienced higher levels of
stress and social disruption than those whose relatives were cared for in institutions.17
15.3.2
Acute hospital
Although several studies have pointed to patients’ requests to die at home, this may reflect a wish that
they never develop a problem that requires hospital admission. Even when no further curative
treatment is anticipated, situations arise that will be best treated in an acute hospital. These include
uncontrolled seizure activity, infection, carer fatigue or difficult symptom control. Brain tumour
patients are likely to have had frequent contact with hospital staff and feel safe and secure there. A
family caring for a patient at home may need respite for many reasons, and an acute hospital may be
the only site available. As the illness progresses and the patient’s strength and time are limited,
hospital outpatient visits for review may become burdensome and should be minimised by liaison
between the hospital specialist, the local palliative care team and the general practitioner.
Palliative care
213
Where patients wish to continue their direct links with a specialist physician or hospital team, an
effective level of contact should be achieved with priority based on patient need, preference and
convenience. Despite the availability of community based palliative care and hospices, many patients
still die in acute care hospitals.18 Attention to symptom control, psychological and emotional support
for the patient and family, and agreement on the goals of care can allow death to occur peacefully in
this setting (see 15.8 Care of the dying patient).
15.3.3
Palliative care unit
Admission to a specialist palliative care unit or hospice bed may be required for symptom assessment
and review of medications if new problems arise, or for terminal care. Admission for respite may be
necessary for family and patient relief. Direct admission from an acute hospital may be indicated for
patients with neurological impairment and symptom burden such that care in the community is not
possible. This may be particularly so for patients suffering from severe neurological disabilities. A
preference for inpatient palliative care rather than home care highlights the importance of having
adequate palliative care beds available.12
15.4
Timing of referral
Early referral to a palliative care service will be facilitated if the palliative care health professionals
are already an integral part of the multidisciplinary treatment team at the cancer centre or treating
hospital.19,20 It is not easy to determine prognosis and methods used to identify survival time have
limitations in accuracy and precision and are therefore not routinely recommended for assessing the
timing of referral to palliative care.21,22 Referral to a palliative care service should be based on need,
not on life expectancy,23 but early referral to a palliative care team allows the establishment of access
and contacts, and exploration of options for future care without the need for immediate decisions.
Early referral will facilitate subsequent continuity of care between hospital, home and hospice and
thus mitigate against any sense of abandonment.24–26 General practitioners who continue to be
involved in the ongoing care of the patient often initiate palliative care. The concept of parallel care,
suggesting a close and continuing cooperation between oncological and palliative services throughout
the course of the illness, is particularly logical for patients with brain tumours. The provision of active
treatment and comfort measures and death preparation in parallel has been called the �mixed
management model’ of end-of-life care.27 The involvement of palliative care professionals does not
preclude the continuation or commencement of chemotherapy, courses of radiotherapy, or surgical or
other procedural interventions aimed at reducing tumour burden or relieving symptoms.28 Such shared
care models reduce concerns of abandonment on behalf of both the doctor and the patient. The
provision of information about a palliative approach may help patients and their families to consider a
palliative approach as active care rather than withdrawal of treatment.29
Recommendation
Level
References
Methods used to identify survival time have limitations in
accuracy and precision and are therefore not routinely
recommended for determining the timing of referral to palliative
care.
I
21,22
15.5
Breaking bad news
Most patients from Western countries prefer some information regarding prognosis when first
diagnosed with a life-limiting illness.30 The amount of information given and the distress that this
causes will vary from patient to patient. Most patients place great emphasis on their relationship with
key health care professionals and prefer �bad news’ information to come from a confident expert.31
Evidence-based clinical practice guidelines for communicating prognosis and end-of-life issues with
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
adults in the advanced stages of a life-limiting illness, and their caregivers, have been published.31
Specific palliative care question prompt lists are also available to help advanced cancer patients and
their caregivers ask appropriate questions about likely outcomes and the intention of treatment.32
Chapter 2 Approach to the patient contains more information on breaking bad news.
Recommendation
Level
References
All patients with advanced progressive life-limiting disease should
be given the opportunity to discuss prognosis and end-of-life
issues.
IV
33
15.6
Symptom management at the end of life
People with brain tumours experience a wide variety of symptoms. The most common physical
symptoms are fatigue, decreased ability to concentrate and remember, loss of independence, nausea,
and pain.34 Added to this are problems relating to neurological deficits and immobility.
The principles of symptom control, used as a standard by clinicians include:
•
thorough assessment of the symptom, including understanding of the meaning ascribed to it by
the patient
•
explanation of the likely cause
•
investigation be undertaken only if it will change the course of action to be followed
•
institution of treatment based on the known or likely aetiology, available options for treatment
and the wishes of the patient
•
monitoring of the response to treatment and modification as necessary.
For guidelines on the management of symptoms, refer to Therapeutic guidelines: palliative care.35
15.6.1
Fatigue
Fatigue �is a distressing, persistent, subjective sense of tiredness or exhaustion related to cancer or
cancer treatment that is not proportional to recent activity and interferes with usual functioning’.36 It is
the most common symptom experienced by patients with brain tumours.34
Assessment of fatigue starts by screening all patients. Some patients expect to feel tired and think that
nothing can be done to improve this symptom. A comprehensive history, physical examination and
limited investigations are needed to look for reversible factors. The pattern of fatigue may vary and
how it is affecting function is perhaps the most important part of the history.
The causes of fatigue are usually multi-factorial, and the aim of the assessment is to identify
potentially treatable contributors and to work out a management plan.
Palliative care
215
Table 15.2
Factors potentially contributing to fatigue
Contributing factor
Examples
Treatment options
Anaemia
anaemia of chronic disease
trial of blood transfusion
Pain
headache
analgesia management as per
WHO guidelines37
Psychological
anxiety, depression, existential
distress
psychosocial interventions such
as support groups, stress
management and relaxation.
treatment of underlying
psychological state
Symptom distress
dyspnoea, nausea and vomiting
treatment of symptom
Electrolyte disturbances
renal, hepatic, endocrine dysfunction
(eg hypothyroidism, hyponatremia)
reversal of abnormality
Nutritional deficiency
anorexia/cachexia syndrome
dexamethasone
megestrol acetate
Infection
urinary tract infections
antibiotics
Sleep disturbance
insomnia
sleeping tablets
non-pharmacological approaches
Medications
sedatives, opioids, diuretics
review of medications
Deconditioning
decreased physical activity
energy conservation
exercise
optimisation of activities of daily
living
As well as specific treatments related to treatable conditions, there are some general management
strategies that can be helpful. These include education (especially of families, who need to
acknowledge that fatigue is not the sole result of decreased food intake), energy conservation,
exercise, optimisation of activities of daily living, psychosocial interventions (such as support groups,
stress management and relaxation).38,39
There are few data about medications that can improve fatigue at the end of life. In general it has not
been shown that any medications have a substantial impact on the symptom, and there is usually a risk
of side effects. Corticosteroids and megestrol acetate have been shown to have a small beneficial
effect in overall quality of life and fatigue.40,41 Psychostimulants (methylphenidate, dexamphetamine),
while showing some promise in non-randomised controlled trials, failed to show a benefit in the only
randomised controlled trial, completed so far.42 If a trial of medication is given it is important to
review the benefits and side effects regularly to ensure their value in an individual situation.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Recommendation
Level
References
Medications (corticosteroids, megestrol acetate) may be trialled
as a treatment of fatigue.
II
40,41
Psychostimulants are not recommended for fatigue, outside of
clinical trials.
II
42
Psychosocial interventions and energy conservation may help
with fatigue.
II
39
15.6.2
Headache
Brain tumour headache can be due to the effect of raised intracranial pressure on parts of the brain
that are sensitive to pain, as well as to invasion of central pain pathways. About half of patients with
brain tumours experience headache.43 The most common characteristics of the headache in one case
series was severe intensity, coming on over days to weeks, lasting hours, intermittent, occurring either
in the morning or night, associated with nausea and vomiting, and throbbing in quality. The site of
pain does not always correlate with the anatomy of the tumour and can even occur on the contralateral
side.
The treatment of headache starts with decreasing oedema and intracranial pressure. Corticosteroids
are the mainstay of treatment. The dose needs to be titrated to pain relief and side effects. It is optimal
to use the lowest dose possible to try to avoid or minimise longer-term debilitating side effects that are
often irreversible in this population. Simple analgesia with paracetamol or non-steroidal antiinflammatories (NSAIDs) can also be used. Care must be taken when using NSAIDs in conjunction
with steroids because of the potential for gastrointestinal side effects. If these measures fail to give
pain relief, opioid analgesics should be used according to the WHO guidelines.37 Opioids should be
used early in those patients in whom the side-effects of steroids are already debilitating.
Assessment of headache and other pain can be difficult in patients who are unable to communicate. It
requires careful assessment of the history of pain, as well as objective physical findings (eg rubbing
head) that seem to improve with the administration of analgesics.
Recommendation
Level
References
Opioids are the analgesics of choice for moderate to severe
cancer pain.
I
44
15.6.3
Seizures
Chapter 11 Symptom management and complications discusses the use of anticonvulsants in general.
The main difficulty in treating seizures at the end of life is the administration of medication. Patients
become drowsy as they deteriorate and their ability to swallow oral medications decreases. Moreover,
they do not usually have cannulas in-situ for intravenous access. Coupled with this is the fact that the
most common anti-epileptic medications (sodium valproate, carbamazepine and phenytoin) can only
be delivered orally or intravenously. Patient who have never had a seizure should not be started on
prophylactic anticonvulsants.45
Changing from oral to alternative routes for the administration of anticonvulsant medication (eg
sublingual delivery) has not been well studied. Medications that have been used �off licence’ by
alternate routes include clonazepam (sublingually or subcutaneously), midazolam (sublingually or
subcutaneously) and diazepam (rectally).
Palliative care
217
Intractable seizures at the end of life
Status epilepticus can be defined as more than 30 minutes of continuous seizure activity, or two or
more sequential seizures without recovery of full consciousness between the seizures.46 The most
common cause in the setting of a brain tumour is progression of disease, but it is important to consider
other factors. These include cerebral haemorrhage, metabolic conditions (especially hypoglycaemia),
medications and substance withdrawal (eg alcohol and benzodiazepines). The approach to treatment is
dependent on the setting of care. Generally, intractable seizures at the end of life are managed in the
home or in a palliative care inpatient facility. The main aim of treatment is to stop the seizure activity
and maintain the quality of life for the patient and family (Table 15.3).35,47 Phenobarbitone is
recommended only when other medications have failed to control seizures. Propofol can only be
delivered intravenously and requires close monitoring. It is not appropriate for use within the
community setting. The effect of rectal diazepam is unpredictable due to inter-patient variation in
absorption. It is important to communicate fully with the family and carers at all times, as seizures can
be very distressing.
Table 15.3
Suggested treatment approach for intractable seizures at home or a palliative care unit
Benzodiazepines
diazepam 5–10mg rectally or 5–10mg IV at the rate of 5mg per minute
midazolam 2.5–5mg subcutaneous injection
clonazepam 1mg subcutaneous or 1mg by slow bolus intravenous injection
followed by a continuous infusion of benzodiazepines
Phenytoin
15–20mg/kg IV, by slow bolus injection (maximum 50mg/minute)
Phenobarbitone
100–200mg subcutaneous or intramuscular injection followed by continuous
subcutaneous infusion of 600–2400mg over 24 hours48
Propofol
Used if all other treatments have been unsuccessful. Expert advice should be
sought.
Nausea and vomiting
Central nervous system tumours may directly or indirectly (through raised intracranial pressure)
stimulate the emetic centre in the brain, leading to nausea and vomiting. If raised intracranial pressure
is suspected, the initial treatment is usually with corticosteroids. Mannitol has been used in resistant
cases. Failure to control nausea with this approach raises the possibility of other causes. The
management in this situation depends on the likely mechanism and follows standard guidelines.49 For
nausea and vomiting not responding to usual medications, other drugs, for example,
methotrimeprazine and cyclizine, can be accessed in hospitalised patients through the Special Access
Scheme.
15.7
Special problems for patients with brain tumours
15.7.1
Feeding, fluids and dysphagia
The conscious state of a patient with a brain tumour will generally deteriorate during the terminal
stage of the illness. This is typically associated with reduced appetite, reduced oral intake and varying
degrees of dysphagia. There may be a risk of aspiration and pneumonia. Aspiration can be reduced by
administering thickened fluids. During the final phase of life, a total inability to swallow is a normal
phenomenon. Given this highly predictable sequence of clinical progression, it is essential that
patients, families and carers are provided with accurate information about issues relating to feeding,
nutrition and fluids. Often these issues can be emotive for families and decision-making can be
difficult for both patients as well as the tending professionals.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
It is important to emphasise to patients and families that nutritional support, either enterally or
parenterally, does not improve morbidity or prolong survival in terminally ill patients.50,51 Evidencebased guidelines have recommended that patients with post-coma unresponsiveness or a minimally
responsive state should not be offered gastrostomy feeding.52 Patients and families typically require
reassurance that the anorexia associated with dying is not uncomfortable. When given this
information, it is unusual for patients or families to request ongoing artificial nutrition in the setting of
an advanced brain tumour. It is essential that the information being provided by all treating
professionals is consistent.
The issue of hydration at the end of life is often controversial in cancer care51,53and in brain tumour
patients it presents unique challenges. The critical challenge is to provide accurate clinical
information and allow for patients or their decision-makers to make informed choices. A palliative
approach to care emphasises that irrespective of the provision of artificial hydration, the patient
should continue to receive high-quality nursing care with attention to pain relief and symptom control
with meticulous attention to mouth care. In brain tumour patients, hydration can worsen the clinical
condition due to increased cerebral oedema. However, if a patient has specific symptoms of unsafe
swallowing but otherwise has a reasonably good functional status, there may be valid arguments to
support parenteral or subcutaneous fluids until the patient’s condition deteriorates to such an extent
that this is no longer appropriate.
In the dying patient, the general consensus is that parenteral hydration is not beneficial.43 Each case
must be considered individually. Recognition of the strong emotional, cultural and spiritual biases of
patients and professionals will assist in tackling this difficult issue. Good decision-making process is
essential. One should not avoid the opportunity to engage with patients and their families and assist
them in making ethical and evidence-based choices about nutrition and hydration.
Recommendation
Level
References
Artificial nutrition is not recommended in patients with advanced
cancer because it does not reduce morbidity or mortality.
I
51
Meticulous attention must be given to mouth care in the dying
patient.
IV
53
Key point:
•
15.7.2
The issue of parenteral hydration in the dying patient remains controversial.
Cognitive dysfunction, depression and acute confusional state
Cognitive impairment is common in patients with brain tumours (70–80%)54 and can profoundly
interfere with work, family and carer relationships, quality of life and even personal identity.55,56 They
are discussed in detail in Chapter 12 Psychosocial care.
Treatment of primary brain tumours with surgery, radiotherapy and chemotherapy and/or adjunctive
medications such as steroids, opioid analgesics, anticonvulsants, anti-emetics and anxiolytics can
result in further negative effects on cognitive function.57–59 Accurate assessment of cognitive
impairment (including attention, memory, learning and information processing speeds, multi-tasking,
visual-spatial ability, mood and personality) at the initial clinic visit and throughout the course of the
illness is vital. Appropriate neuropsychological tools include the Neuro-behavioural Cognitive Status
Examination60 and the Addenbrooke’s Cognitive Examination61. Treatment effects can be subtle and
may not be captured by blunt measurement tools such as the Mini-Mental State Examination
(MMSE). Most research to date on treatment effects has been focused on gross endpoint changes in
Palliative care
219
the MMSE rather than more subtle endpoints such as improvement in neurocognitive function
(memory, verbal fluency, visual–motor speed, executive function, language and reasoning) or delays
in neurocognitive progression.62
Improvements in prognosis in some patients following radiotherapy and chemotherapy has
implications for palliative care and introduces the need for active early rehabilitation based on a clear
assessment and proactive search for cognitive deficits according to tumour location63 (see Table 15.4).
See also Chapter 13 Rehabilitation.
Table 15.4
Cognitive deficits according to tumour location
Tumour site
Common deficits
Left hemisphere
Language, verbal memory and reasoning, right-sided strength and
dexterity
Right hemisphere
Visual perception and construction, left hemi-spatial inattention, leftsided strength and dexterity
Anterior (frontal lobes)
Executive functions
There is increasing evidence that active rehabilitation in patients with brain tumours is as effective in
the earlier phases of their disease as it is for patients post-stroke or traumatic brain injury.54,64
Rehabilitation programmes have been based on multidisciplinary cognitive rehabilitation principles
that include restoration (cognitive training, memory rehearsal, etc), substitution (compensatory
devices and strategies), restructuring (changing expectations and environmental settings) and coping
with personal identity crises (reminiscence therapy or psychotherapy groups centred on participant
past narratives exploration).55,65
Several pharmacological interventions have been tried with variable success. These include
psychostimulants, for example, methylphenidate for attention, cognitive processing speed and mood
enhancement66,67; antipsychotics, for example, risperidone for behavioural disturbance68; and
acetylcholinesterase inhibitors, for example, donepezil in irradiated brain tumour patients with
possible deficits in neurocognitive processing.69
The management of elderly poor-prognosis patients remains a challenge. Comprehensive cognitive
assessment at presentation is vital to establish a baseline and to provide adequate support. The use of
steroids and mannitol to control peri-tumoural oedema combined with physiotherapy to maintain
function may have a significant positive effect on quality of life.70 New and more specific indicators,
such as Quality Adjusted Survival Parameters, which are able to balance the benefits against the side
effects of treatment are indicated for this elderly population.71
Not all impairment of cognitive function will be related to the primary disease. There are multiple
other potential causes of impaired function in patients with brain tumours, for example, urinary tract
infection, drug toxicity, substance withdrawal. Any potentially reversible cause should be actively
sought and treated appropriately.
15.7.3
Bowel and bladder problems
Comprehensive bowel care commences with a detailed history of past and present bowel habit,
instigation of a bowel chart and re-evaluation of current aperients. Bowel management for brain
tumour patients may be complicated by the patient’s reduced mobility, neurological deficits and
inability to communicate. Carer and staff education in using equipment, for example, hoist and slings
for transfer to commode or toilet, is essential. As well as having the patient in a sitting position, carers
should ensure there is provision for privacy and safety.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Brain tumour patients are at increased risk of constipation due to reduced mobility and low oral intake
secondary to dysphagia and/or drowsiness, as well as the medications they may be receiving (eg
opioids, antidepressants), their reduced mobility and reduced oral fluid intake caused by dysphagia
and/or drowsiness. Routine bowel management review is essential. A digital rectal examination plus
physical examination and a plain film of the abdomen may be required to ascertain the site and degree
of the constipation. Aperients should be reviewed regularly. Consider the use of a constipation flowchart.72 Faecal impaction is the accumulation of compacted faecal material in the rectum or colon. The
patient may develop symptoms such as paradoxical diarrhoea with incontinence, anorexia, nausea
and/or vomiting. They may also have urinary frequency, retention or overflow of urine.
The passage of some stool does not rule out the presence of faecal impaction. The management of
faecal impaction requires �per rectum’ interventions (enemas or suppositories) as well as aperients.
Abdominal x-ray may be required for diagnosis and may need to be repeated to ascertain the impact
of management strategies. Manual evacuation is occasionally necessary; patients should have
appropriate sedation prior to this procedure.
During the terminal phase, bowel evacuation in a drowsy, bed-bound patient should be regulated with
suppositories prior to bed bath. The use of incontinence aids provides comfort and security for the
patient.
Urinary incontinence, or the failure to control urine, may be due to many factors including retention
with overflow or be associated with neurological dysfunction. The patient may have expressive
dysphasia and therefore be unable to communicate the need for toileting or have reduced mobility
resulting in urge incontinence.
Assessment of urinary incontinence includes history taking, physical examination, urinalysis and the
elimination of other predisposing causes of incontinence including urinary tract infections and steroidinduced diabetes. Incontinence aids ranging from discrete panty liners to continence pants may be
necessary. Condom drainage or catheterisation should be considered.
This may eliminate the incontinence but may not affect the sensation of urinary urgency. Patients with
short-term memory loss, hemiplegia and urinary frequency or incontinence may experience multiple
episodes of nocturia. This can be exceedingly difficult to manage. The patient will be at increased risk
of falls and both patient and carer will experience sleep deprivation. Respite for carers may be
indicated.
15.7.4
Pressure areas
The terms �pressure sores’, �decubitus ulcers’, �bed sores’, �pressure necrosis’ and �ischaemic ulcers�
describe any lesion caused by unrelieved pressure damaging underlying tissue.72 The risk of any
individual patient developing a pressure ulcer is assessed according to the Norton Risk Assessment or
the Waterlow Pressure Sore Prevention/Treatment policy.73 Some degree of impairment of skin
integrity is almost inevitable in a bed-bound patient. Once present, pressure ulcers are very difficult to
heal and can contribute significantly to the morbidity of a bed-bound patient. In the extreme, they are
a constant source of pain and potential infection and can impose a significant burden on carers.
Predisposing risk factors in brain tumour patients are impaired mobility, sensory perception and
inactivity. The patients are often Cushingoid and hemiparetic; this increases the risk of pressure ulcers
caused by friction and shearing of skin tissue that can occur when repositioning patients.
Prevention of pressure ulcers is essential. Simple measures include turning every two hours, sheepskin rugs and resting the heels on water-filled gloves. Referral of patients to the occupational therapist
for assessment of equipment requirements is recommended. Once established, pressure ulcers can be
difficult to heal, especially after long-term steroid use and immobility.
Palliative care
221
Ulcer management should be directed by a wound care management nurse or stomal-therapist if
available. Patients may require a breakthrough dose of analgesia prior to dressing procedures. There is
some evidence to support the use of topical opioids and local anaesthetic agents for chronic wound
pain associated with dressing changes or debridement.74
Key point:
• Opioids applied topically (eg morphine paste or liquid) can relieve the pain associated
with pressure area wound care.
15.7.5
Corticosteroid use
Steroids are used almost routinely in patients with primary brain tumours and have both specific and
nonspecific indications.
•
Specific indications: (see Chapter 11 Symptom management and complications) These relate to
the palliation of symptoms associated with raised intracranial pressure. Oedema resulting from a
breakdown in the normal blood–brain barrier in patients with brain tumours causes an increase in
intracranial pressure and neurological dysfunction, presumably because of ischaemia from the
mass effect. Associated symptoms include headache, nausea and vomiting and a decreased level
of consciousness. Corticosteroids frequently lead to a rapid and substantial improvement in both
neurological dysfunction and symptoms related to this peritumoural oedema. The exact
mechanism for this is unknown.75 Low-dose dexamethasone (4mg) has been shown to be as
effective as 16mg in the palliation of symptoms of brain tumour oedema in patients with
metastatic brain disease.76 Higher doses may be needed for primary brain tumours.
•
Nonspecific indications: steroids are used to palliate symptoms commonly associated with
advanced malignant disease such as decreased appetite, pain, dyspnoea, low mood and general
fatigue. Steroids have been shown to be similar to megestrol acetate with respect to appetite
enhancement and non-fluid weight gain77 and superior to placebo in controlling pain.78 The
evidence of benefit for all other nonspecific indications has not been tested in a controlled setting.
Dexamethasone is generally used in routine clinical practice because of its relative low
mineralocorticoid and high glucocorticoid potency compared to other steroids. It may be administered
orally or parenterally. The dose is individualised to the patient’s needs and is usually given in the
morning in an attempt to prevent insomnia. This is unlikely to protect against nocturnal agitation
however, as the biological half-life of the drug is very long (36–54 hours).
The prolonged use of steroids must be balanced against the potential for side-effects (Table 15.5) that
are related to dose and length of treatment.79–82 Approximately one-half of patients treated with
steroids over a prolonged period develop disturbed glucose metabolism that may persist following
withdrawal of the drug.83 The incidence of severe psychiatric illness is uncommon at low doses but
increases to almost 20% of patients treated with more than 12mg/day dexamethasone.84 Analyses of
the magnitude of the risk of steroid-induced peptic ulcers provide conflicting results.75 Most patients
treated with conventional doses of steroids, (for example, 16mg of dexamethasone per day for more
than 2–3 weeks) develop some degree of myopathy.79 This can significantly hinder mobility and the
ability to care for patients at home. Moreover, the benefit of steroids may diminish with time85 either
because of loss of effect of the drug or progression of disease.
Best practice is to reduce the dose slowly to the lowest effective dose and to monitor side effects
continuously.86 Benefit should be weighed against toxicity. Generalised dose schemes should not be
used, but dosage should be adapted to each patient’s individual needs.87 Some advocate pulsed doses
(a short course of moderate dose dexamethasone) rather than prolonged courses, to relieve symptoms
and minimise side effects. The use of steroids at the end of life is controversial. Many clinicians
discontinue the drug when the patient is no longer able to take tablets by mouth. Others continue to
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
deliver a tapering dose parenterally in an attempt to prevent symptoms of steroid withdrawal. The
continued treatment with increasing doses of steroids in the terminal phase may serve only to prolong
death rather than contribute to quality of life.
Key point:
•
Patients should be maintained on the lowest possible effective steroid dose to minimise
side effects.
Key points:
With regard to steroids the clinician should;
•
Dose according to each patient’s individual needs.
•
Consider pulsed rather than continuous treatment.
•
Monitor continuously for side effects.
•
If no longer of benefit, wean down slowly and discontinue.
•
Consider prophylactic nystatin and gastroprotection in all patients, especially those with
added risk factors.
Table 15.5
Steroid side-effects
Cushingoid habitus—moon face, buffalo hump
Skin changes—striae, acne, tendency to bruising, skin frailty, poor wound healing
Proximal myopathy
Psychological disturbance—restlessness, agitation, anxiety, sleep disturbance, behavioural change,
frank psychosis
Hyperglycaemia and glycosuria
Peripheral oedema
Gastrointestinal toxicity
Infections—oral candidiasis, increased susceptibility to infections
15.8
Care of the dying patient
The unique needs of dying patients must be considered, their comfort maximised and their dignity
preserved. Palliative Care Australia Standards.4
Common themes contributing to a good death include control, autonomy and independence with
respect to pain and symptom control, place of death, who should be present at the time of death and
the maintenance of privacy. Access to information and expertise, as well as spiritual and emotional
support, is also important.88 The most important components of a good death, according to focus
group work with health professionals, patients and carers, are good pain and symptom management,
clear decision making, preparation for death, completion, contributing to others, and affirmation of the
whole person.89 Patients and families tend to fear �bad’ dying more than death itself. Attributes of a
Palliative care
223
�bad’ death include the lack of opportunity to plan ahead and arrange personal affairs. Issues that
contribute to the sub-optimal care of patients dying in hospital include a lack of open communication,
difficulties in accurate prognostication and a lack of planning of end-of-life care.90
Hospice-type care is cited as the �bench-mark’ and should be available across all settings.91
Systems for managing end-of-life care and mortality management should be in place in all health
institutions (Australian Council of Health Care Standards).92
Strategies that have been designed to improve end-of-life care include the increasing acceptance and
use of advance care directives, the education of health care professionals in principles of �dying well’
and the development of integrated care pathways (ICPs) for the care of the dying.91 These
multidisciplinary care plans are patient-centred and address not only the physical but also the
important psychosocial, spiritual and practical issues that surround death. They detail the essential
goals necessary for the care of dying patient (Table 15.6) and empower non-specialist (generalist)
palliative care workers in the palliative approach. An essential component of the pathway is a change
of emphasis of care away from life-saving measures at all cost to the best supportive care of a dying
patient.
Making a diagnosis of �dying’ is not always easy. Moreover, while it may be clear to relatives, carers
and other health professionals that a patient is dying, the treating team may be loath to accept
�medical failure’ and change the goals of care. The palliative care team may facilitate the change in
emphasis. Typically, a patient who is entering the terminal phase is bed-bound and withdrawn, with
increasing drowsiness, weakness and decreased mobility. Dying patients are unable to take food or
fluids and may become restless, confused or �terminally agitated’. Patients with advanced disease who
deteriorate and appear to have entered a terminal phase may have an easily reversible cause for their
deterioration, for example sepsis or opioid toxicity. A reversible cause is more likely if there has been
a rapid deterioration from a previously good quality of life.
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
Goals of care for patients in the dying phase93
Table 15.6
Domain
Goal
Comfort measures
1
Current medication assessed and non-essentials discontinued
2
As-required subcutaneous drugs written up according to
protocol (pain, agitation, respiratory tract secretions, nausea,
vomiting)
3
Discontinue inappropriate interventions (blood tests,
antibiotics, intravenous fluids or drugs, turning regimens,
vital signs)
4
Document �not for cardiopulmonary resuscitation’
5
Ability to communicate in English assessed as adequate
(translator not needed)
Psychological and insight
issues
6
Insight into condition assessed
Religious and spiritual
support
7
Religious and spiritual needs assessed with patient and
family
Communication with family
and others
8
Identify how family or other people involved are to be
informed of patient’s impending death
9
Family or other people involved given relevant hospital
information about access and contacts
Communication with
primary health care team
Care after death
15.8.1
10
General practitioner is aware of patient’s condition
11
Plan of care explained and discussed with patient and family
12
Family or other people involved express understanding of
plan of care.
13
General practitioner informed
14
Procedure for laying out explained
15
Procedure following death discussed
16
Family given information re procedures
17
Policy about valuables in place
18
Necessary documentation given to family
19
Bereavement leaflet given
Resuscitation and advance directives
Individuals prepare for death by completing any �unfinished business’, for example, signing wills,
contacting loved ones, appointing a power of attorney. Any advanced health directive should be
honoured and issues surrounding resuscitation discussed. Early and ongoing advanced care planning
is important and health practitioners should initiate end-of-life conversations and advanced care
planning as early as appropriate. Patients’ wishes regarding practical issues such as parenteral feeding,
antibiotics and intravenous fluids should be explored. Each individual should also be given the
opportunity to voice their wishes regarding desired place of death and who should be present at the
time of death. These discussions can only follow frank and open discussions with patients and
families about the current medical status and prognosis.
Palliative care
225
Occasionally patients and/or their relatives or carers will express a wish that the patient die or have
their early death facilitated. Patients requesting euthanasia are often asking for an end of their
suffering rather than for an end of their life. Such requests are often not repeated when distressing
symptoms are addressed and controlled. Request for euthanasia has been linked to depression.94
Recommendation
Level
References
All patients requesting euthanasia should be thoroughly assessed
in terms of their symptoms and mental wellbeing, and in
particular, for evidence of depression. All symptoms should be
managed, including offering treatment and counselling for
depression if present.
III
94
Key point:
•
Early and ongoing advanced care planning is important and health practitioners should
initiate end-of-life conversations and advanced care planning as early as appropriate.
15.8.2
Symptom management in dying patients
The aim of palliative care in the terminal phase is to provide good symptom control for the patient,
support for their carers, and to neither hasten death nor prolong the dying phase. As death approaches,
nonessential medications should be discontinued and all medicines essential for the maintenance of
symptom control continued and delivered by an appropriate route. While most drugs are delivered
subcutaneously in a 24-hour infusion, the rectal, sublingual and transdermal routes provide an
alternative option. Pain is the most common and most feared symptom of advanced disease and
analgesics must always be continued. Adequate pain relief does not hasten death.95 Similarly,
antiemetics, corticosteroids, antipsychotics and sedatives may all be necessary for symptom relief.96
Anticholinergics should be available in anticipation of the development of noisy breathing secondary
to retained secretions in the large airways (�death rattle’).Terminal restlessness is a state of agitation
and unease often witnessed in dying patients. The reversible causes of this agitation (eg urinary
retention, faecal impaction or pain) should be actively sought and treated. The cause is often unknown
or unclear, and sedation is used as a means of symptom control. All opioids and sedatives are titrated
carefully according to symptom response. Guidelines for symptom management in the dying patient
are detailed in Therapeutic guidelines: palliative care.35
Recommendation
Level
References
Non-essential medications should be discontinued and essential
medications should be prescribed by an appropriate route.
IV
96
Key point:
•
Pain is the most common and most feared symptom of advanced disease and
analgesics must always be continued.
15.8.3
Place of death
The majority of people in the general population and those with cancer would prefer to die at
home.97,98 Despite this, only a minority of patients die at home.99 This reflects the changing needs of a
patient during their illness trajectory. Some of the factors that make it more likely the patient is able to
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
die at home include involvement of a community palliative care service, perceived family support,
and avoidance of hospitalisation.100,101 It is important to determine whether the patient and family
have a preferred place of death and to monitor this during their illness. If that preference is for dying
at home, involvement of a community palliative care service can make this more likely to occur.100,101
Key point:
• Involvement of a community palliative care service makes it more likely that the patient
will die at home.
15.9
Bereavement and support of families
Anticipatory grief is the process by which friends and family come to terms with the potential loss of
a significant person. This may well be of particular relevance in patients with slowly progressive brain
tumours. Patients and relatives can be supported through open discussion, clarification of likely
outcomes and life review processes.102
Spiritual and religious support with an appropriate cultural focus should be offered both to the patient,
and to the family after death in the context of bereavement support.103
As the patient enters the terminal phase, increasing distress is experienced as patients and families
anticipate and prepare for death. An individualised approach to bereavement care is required as
distress experienced by the patient and each family member is different in its nature, intensity and
duration.104
On admission to palliative care, an assessment will assist the team in individualising pre-death support
and bereavement care, helping long-term adjustment. Useful assessment criteria include age of patient
and family, coping mechanisms, evidence of mental illness and cumulative multiple losses, perceived
support and degree of family cohesion. Following death, other factors to consider include relationship
and the nature of that relationship to the deceased, nature of death and whether the death was
unexpected or perceived as traumatic.105
Common fears for people in the end stages of life include uncontrolled symptoms and �being a
burden’. Honest and appropriately paced communication will often assist in minimising these fears as
death approaches. Support includes the provision of information that assists the patient and family in
discussing treatment decisions and bodily changes. Additional skills such as aiding communication in
families, opening conversations with children, acknowledging the patient’s life contributions,
exploring spiritual and religious dimensions, and preparing the funeral together, can also help to
prepare for death. Discussion and completion of documents, such as power of attorney and advanced
health directives, can provide guidance for treatment and an understanding of the desires of the patient
and family.
Following death, most but not all grieving people experience numbness, intense distress, anxiety,
yearning and loss of concentration. In addition, physical signs of stress, sleep and appetite
disturbances can occur. Not all bereaved will require psychological interventions as protective factors
such as positive coping patterns, an optimistic personality, social support and faith will assist in
buffering against the stress of bereavement. However health professionals who are aware of the
psychological reactions and possible social and cultural influences may assist the bereaved through
normalising and providing psycho-education about the constantly changing responses. Assisting the
bereaved in coping with the loss and in making adjustments to changes in life through encouraging
them to share positive memories, establish goals and plan activities that provide pleasure can help to
promote wellbeing. Complicated grief will occur for a small percentage of the bereaved, and further
Palliative care
227
studies are required to understand interventions that are helpful for this group. However, health
professionals can help the bereaved to identify early warning signs and seek help. These signs may
include persistent hopelessness, depression, suicidal ideation, continuing physical symptoms, lack of
ability to function and misuse of drugs.106–108 For family members who are dealing with challenging
bereavement issues (such as complicated grief) various support systems are available including
oncology or palliative care social workers, community nurses or psychologists who knew the patient.
Alternatively, the family member may seek help from their own GP who may refer them on to a
psychiatrist or psychologist if needed.
Key points:
Risk factors for complicated grief include:105
•
Male gender
•
Lack of coping mechanisms
•
History of mental illness
•
Multiple losses
•
Intense brief relationship with deceased
•
Lack of support and family cohesion
•
Unexpected or traumatic death
•
Financial difficulties
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
APPENDIX 1 WORKING PARTY MEMBERSHIP AND
CONTRIBUTORS TO GUIDELINES
Brain Tumour Guidelines Working Party
Professor Michael Barton OAM
Professor Bruce Barraclough AO
Radiation Oncology, NSW (Chair)
Medical Director, ACN (until 31 December
2007) NSW
Dr Michael Bynevelt
Associate Professor Frances Boyle AM
Dr Lawrence Cher
Associate Professor Andrew Cole
Ms Laraine Cross
Dr Kate Drummond
Dr Ron Freilich
Professor Janet Hardy
Dr Elizabeth Hovey
Dr Margot Lehman
Dr Anna Nowak
Dr William Patterson
Emeritus Professor Tom Reeve AC CBE
Radiology, WA
Medical Oncology, NSW
Neurology, VIC
Rehabilitation Medicine, NSW
Social Work / Brain Tumour Australia, NSW
Neurosurgery, VIC
Neurology, VIC
Palliative care, QLD
Medical Oncology, NSW (Project Officer)
Radiation Oncology, QLD
Medical Oncology, WA
Medical Oncology, SA
Senior Medical Advisor-ACN, NSW
(Convenor)
Dr Michael Rodriguez
Professor Mark Rosenthal
Dr Gail Ryan
Dr Sally Smith
Mr Denis Strangman
Dr Charles Teo
Associate Professor Jane Turner
Dr David Walker
Dr Jonathan Wood
Dr Helen Wheeler
Ms Christine Vuletich
Ms Alice Winter-Irving
Neuropathology, NSW
Medical Oncology, VIC
Radiation Oncology, VIC
Public Health, NSW
Consumer / International Brain Tumour Alliance,
ACT
Neurosurgery, NSW
Psychiatry, QLD
Neurosurgery, QLD
Neurology, NSW
Medical Oncology, NSW
ACN Secretariat
ACN Secretariat
Chapter leaders and their sub-committees
1. Setting the Scene
Dr Sally Smith*
Professor Michael Barton OAM
Public Health, NSW
Radiation Oncology, NSW
2. Approach to Patient
Dr Elizabeth Hovey*
Associate Professor Frances Boyle AM
Ms Laraine Cross
Dr Kate Drummond
Dr Michael Jefford
Ms Louise Sharpe
Ms Rhea Stein
Associate Professor Jane Turner
Medical Oncology, NSW
Medical Oncology, NSW
Social Work / Brain Tumour Australia, NSW
Neurosurgery, VIC
Medical Oncology, VIC
Psycho-oncology, NSW
Psycho-oncology, NSW
Psycho-oncology, QLD
Appendices
235
3. Clinical Trials and Research
Dr Anna Nowak*
Associate Professor Martin Stockler
Dr Nik Zeps
Medical Oncology, WA
Medical Oncology, and Public Health, NSW
Basic Science and, Medical Ethics
4. Clinical Presentation
Dr Ron Freilich*
Dr Marion Harris
Dr Helene Roberts
Dr Anita Vinton
Neurology, VIC
Medical Oncologist, VIC
Neurologist, VIC
Neurologist, VIC
5. Imaging
Dr Michael Bynevelt*
Radiology, WA
6. Diagnosis and Pathology
Dr Michael Rodriguez*
Associate Professor Michael Gonzales
Neuropathology, NSW
Neuropathology, VIC
7. Low grade astrocytomas
Dr Charles Teo*
Dr Ross Jennens
Dr Gail Ryan
Dr David Walker
Neurosurgery, NSW
Medical Oncology, VIC
Radiation Oncology, VIC
Neurosurgery, QLD
8. High Grade Astrocytomas
Dr Kate Drummond*
Professor Michael Barton OAM
Dr Guy Bryant
Dr Craig Carden
Dr Raymond Cook
Dr Michael Dally
Dr Adam Fowler
Dr Margot Lehman
Dr Jason Lickliter
Dr Bulent Omay
Professor Mark Rosenthal
Neurosurgery, VIC
Radiation Oncology, NSW
Radiation Oncology QLD
Medical Oncology, VIC
Neurosurgery, NSW
Radiation Oncology, VIC
Neurosurgery Trainee, NSW
Radiation Oncology, QLD
Medical Oncology, VIC
Neurosurgery, VIC (Turkey)
Medical Oncology, VIC
9. Oligodendrogliomas
Dr Lawrence Cher*
Dr Rosemary Harrup
Dr Renate Kalnins
Dr Anna Nowak
Dr Mandy Taylor
236
Neurology, VIC
Medical Oncology/Haematology, TAS
Anatomical Pathology, VIC
Medical Oncology, WA
Radiation Oncology, WA
Clinical practice guidelines for the management of astrocytoma and oligodendroglioma in adults
10. Complementary, alternative and unproven therapy
Dr William Patterson*
Emeritus Professor Tom Reeve AC CBE
Medical Oncology, SA
Senior Medical Advisor-ACN, NSW
(Convenor)
Mr Denis Strangman
Consumer / International Brain Tumour Alliance,
ACT
11. Symptom management and complications
Dr Jonathan Wood*
Dr Neil Anderson
Dr Rob Lindeman
Associate Professor Ernest Somerville
Dr John Sullivan
Dr Oril Wargon
Neurology, NSW
Neurology, Auckland New Zealand
Haematology, NSW
Neurology, NSW
Dermatology, NSW
Dermatology, NSW
12. Psychosocial care
Associate Professor Jane Turner*
Ms Georgina Haysom
Dr Stephen Lee
Psychiatry, QLD
Senior Solicitor, Avant Insurance Limited
Neuropsychology, NSW
13. Rehabilitation
Associate Professor Andrew Cole*
Dr Greg Bowring
Dr David Eckerman
Professor Janet Hardy
Dr Neil Johns
Dr Kathy McCarthy
Ms Ornissa Naidoo
Rehabilitation Medicine, NSW
Rehabilitation Medicine, NSW
Rehabilitation Medicine, QLD
Palliative care, QLD
Rehabilitation Medicine, VIC
Rehabilitation Medicine, NSW
Occupational Therapy, QLD
14. Follow-up
Dr Margot Lehman*
Dr Stephen Stuckey
Radiation Oncology, QLD
Radiation Oncology, VIC
15. Palliative care
Professor Janet Hardy*
Dr Mark Deuble
Dr Phillip Good
Ms Ornissa Naidoo
Ms Gabrielle O’Connor
Associate Professor Rohan Vora
Ms Julie Walters
Palliative Care, QLD
Palliative Care, QLD
Palliative Care, NSW
Occupational Therapy, QLD
Nursing, Palliative Care/Neuro-oncology, VIC
Palliative Medicine, QLD
Liaison Librarian, QLD
Glossary
Emeritus Professor Tom Reeve AC CBE*
Senior Medical Advisor, ACN / Convenor,
Working Party, NSW
Professor Michael Barton OAM
Dr Elizabeth Hovey
Radiation Oncology, NSW
Medical Oncology, NSW
* Chapter leader
Appendices
237
Review Process:
Internal Reviewers
Professor Michael Barton OAM
Dr Elizabeth Hovey
Dr Anna Nowak
Dr Sally Smith
Mr Denis Strangman
Radiation Oncology, NSW
Medical Oncology, NSW
Medical Oncology, WA
Public Health, NSW
Consumer, ACT
Invited External Reviewers
Dr Meera Agar
Dr Helen Austin
Professor Susan Chang
Dr Di Clifton
Professor Noel Dan
Professor Robert DePompolo
Associate Professor Michael Fearnside AM
Professor Graham Giles
Associate Professor Afaf Girgis
Professor Paul Glare
Dr Eng-Siew Koh
Mr Denis Strangman
Mr Ross Symons
Dr Mo Mo Tin
External Expert Review Panel
Professor Michael Frommer (Chair)
Associate Professor Frances Boyle AM
Dr Michael Buckland
Ms Kaye Duffy OAM
Dr Monika Janda
Dr Elizabeth Hovey
Ms Sally Payne
Emeritus Professor Tom Reeve AC CBE
Associate Professor Daniel Roos
Associate Professor Jeffrey Rosenfeld
Dr Brindha Shivalingam
Project Officer, BTGLWP*
Convenor, BTGLWP*
Acknowledgement
These guidelines would not have been possible without the generous donation received from Mr
Steven Newton in memory of his late wife Valerie Newton.
This generous donation has been further supported by funding received from the Cancer Council
Australia.
Ms Hester Gascoigne of Hester Gascoigne and Associates, Canberra for editing the draft document for
public consultation.
Miss Mary Russell, Freelance Indexer, Caulfield Victoria, for indexing the Guidelines.
238
Clinical practice guidelines for the management of astrocytoma and oligodendroglioma in adults
APPENDIX 2 – GLOSSARY AND ABBREVIATIONS
Glossary
Activated partial
thromboplastin time
(APTT)
APTT measures the time necessary to generate fibrin from initiation of the
intrinsic pathway.
Astrocytoma
A tumour of central nervous system composed of astrocytes.
Cognitive
Mind function and awareness, perception, thinking and memory.
D- dimer
A test to detect the production of fibrin breakdown products following conversion
of fibrinogen to fibrin. This is frequently elevated in the setting of
thromboembolism.
Fluorescence in situ
hybridization (FISH)
This is a pathology test that measures the amount of a certain gene in cells.
Glioblastoma multiforme
(GBM)
The most malignant type of glioma. Grade IV on WHO classification of gliomas.
Glioma
A tumour of neuroglia at any stage of development.
Gray
The gray (symbol: Gy) is the SI unit of absorbed radiation dose. One gray is the
absorption of one joule of radiation energy by one kilogram of matter.
Hemiparesis
Partial paralysis or muscular weakness involving half of the body.
Hemiplegia
Paralysis of one side of the body.
IVC filter
A filtration device inserted in the inferior vena cava to prevent pulmonary emboli.
Karnofsky performance
status.
A performance measure for rating the ability of a person to perform usual
activities, evaluating a patient's progress after a therapeutic procedure, and
determining a patient's suitability for therapy. It is used most commonly in the
prognosis of cancer therapy, usually after chemotherapy and customarily
administered before and after therapy.
Li Fraumeni Syndrome
A rare autosomal dominant hereditary disorder. Li-Fraumeni syndrome increases
greatly the susceptibility to cancer. The syndrome is due to a mutation in the p53
tumor suppressor gene, which normally helps control cell growth.
Magnetic Resonance
Spectroscopy
Magnetic resonance spectroscopy (MRS) is different from MRI because MRS uses
a continuous band of radio wave frequencies to excite hydrogen atoms in a variety
of chemical compounds other than water. These compounds absorb and emit radio
energy at characteristic frequencies, or spectra that can be used to identify them.
Oligodendroglioma
A tumour of oligodendrocytes. Majority in white matter of the brain. Can be low
grade (grade II) or high grade (usually grade III)
PCV
Procarbazine plus lomustine (CCNU) plus vincristine. This is a combination of
three types of chemotherapy that has been administered predominantly in the
scenario of oligodendroglioma (though also in the setting of astrocytoma in the
past).
Technetium
99m
Wiki
A website that uses wiki software, allowing the easy creation and editing of any
number of interlinked Web pages within the browser. Wikis are often used to
create collaborative websites, to power community websites, and for note taking.
Tc diethylenetriamine pentaacetate. A radionuclide chelate complex used for
nuclear medicine imaging and function testing; also known as 99mTc pentatate
[diethylene triamine pentaacetic acid].
Appendices
239
Abbreviations
18
FFDG
201
Ti
18
F-Fluorodeoxyglucose
Thallium
99m TcDTPA
Technetium 99mTc diethylenetriamine pentaacetate
ADC
Apparent diffusion coefficient
AED
Anti-epileptic drug
AF
Accelerated fraction
AGPS
Australian Government Printing Services
AIHW
Australian Institute of Health and Welfare
APTT
Activated partial thromboplastin time.
AUC
Area under the curve
AYLL
Average person years of life lost
BCNU
bischloroethylnitrosourea (Carmustine)
CAM
Complementary and alternative therapy
CBV
Cerebral blood volume
CBZ
Carbamezepine
CCNU
cyclohexylchloroethylnitrosourea (Lomustine)
CI
Confidence Interval
CNS
Central nervous system
CSF
Cerebrospinal fluid
CT
Computerised Tomography (imaging device)
CTV
Clinical target volume
DNA
Deoxyribonucleic acid
DTI
Diffusor tensor imaging
DTIC
Dacarbazine (chemotherapy)
DVT
Deep venous thrombosis
DYF Quick
A cytological stain
ECOG
Eastern Cooperative Oncology Group
EIAED
Enzyme-inducing anti-epileptic drug
FISH
Fluorescence in situ hybridization.
FLAIR
Fluid attenuated inversion recovery (MRI)
GBM
Glioblastoma multiforme
GBP
Gabapentin, an antiepileptic drug
GTV
Gross tumour volume
GuMRI
Gadolinium enhanced magnetic resonance imaging
Gy
Gray
240
Clinical practice guidelines for the management of astrocytoma and oligodendroglioma in adults
HF
Hyperfractionation
HGG
High grade glioma
HIT
Heparin induced thrombocytopaenia
HITT
Heparin-induced thrombocytopenia and thrombosis
HNPCC
Hereditary non-polyposis colon cancer
HR
Hazard Ratio
ICU
Intensive care unit
IFRT
Involved field radiotherapy
iMRI
Intraoperative MRI
IPC
Intermittent pneumatic compression
IQ
Intelligence quotient
IV
Intravenous
IVC
Inferior vena cava
KPS
Karnofsky performance status.
LEV
Leviteracitam, an anti-epileptic drug
LFS
Li Fraumeni Syndrome
LGA
Low grade astrocytoma
LGG
Low grade glioma
LMWHs
Low molecular weight heparins
LOH
Loss of heterozygosity. (Referring to chromosomal alterations or
segmental losses)
LTG
Lamotrigine; a newer generation anti-epileptic drug
MDC
Multidisciplinary care
Methyl CCNU
methylcyclohexylchloroethylnitrosourea (semustine)
MGMT
O6-methylguanine-DNA methyltransferase
MRC
United Kingdom Medical Research Council
MRI
Magnetic Resonance Imaging
MRS
Magnetic Resonance Spectroscopy
NCCTG
North Central Cancer Treatment Group
NHMRC
National Health and Medical Research Council
NSAID
Non-steroidal anti-inflammatory drug
OA
Oligoastrocytoma
OG
Oligodendroglioma
ORR
Overall Response Rate
OS
Overall Survival
OXC
Oxcarbazepine, an antiepileptic drug
Appendices
241
PAP
Perioxidase anti-perioxidase cytological stain
PBS
Pharmaceutical Benefits Scheme
PCV
Procarbazine plus lomustine (CCNU) plus vincristine.
PE
Pulmonary embolism
PET
Positron Emission Tomography.
PFS
Progression Free Survival
PHT
Phenytoin, an anti-epileptic drug
PRG
Pregabalin, an anti-epileptic (or anticonvulsant) drug
QOL
Quality of life
RBI
Radio-labelled compound- eg 3 -(4-iodophenyl)-2 (tricarbonylrheniumcyclopentadienylcarboxym ethyl)tropane
(RBI-211)
rCBV
Relative Cerebral Blood Volume (alternately Regional Cerebral
Blood Volume)
RCT
Randomised Clinical Trial
RPA
Recursive partitioning analysis
RTOG
Radiation Therapy Oncology Group. This is an international
cooperative trial group participating in trials assessing radiation
therapy in different settings.
SES
Socioeconomic status
SPECT
Single Photon Emission Computed Tomography
T1
Signal characteristics of magnetic resonance
T2
Signal characteristics of magnetic resonance
TD
Tolerance dose of radiation (defined as 5% complication rate in
five years (TD5/5))
TGB
Tiagibine, an anti-epileptic drug
TTP
Time to progression
TPM
Topiramate, an anti-epileptic drug
UFH
Unfractionated Heparin
V/Q
Ventilation-Perfusion scan.
VEGF
Vascular endothelial growth factor
VPA
Valproic acid, also known as sodium valproate
VTE
Venous thromboembolism
WBRT
Whole brain radiotherapy
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Clinical practice guidelines for the management of astrocytoma and oligodendroglioma in adults
APPENDIX 3
GUIDELINES DEVELOPMENT PROCESS
Clinical Practice Guidelines for the Management of Adult Gliomas,
Astrocytomas and Oligodendroglioma
Purpose, scope and development process of the Guidelines:
These Guidelines have been developed to provide information on malignant adult brain tumours
(specifically gliomas) to medical practitioners and interested community members.
The aim is to improve the level of practice and understanding in a health area that causes considerable
community anxiety.
Brain tumours also contribute heavily through costs of hospital, home and community management to
the budget of the Australian health care system. They impose the highest economic burden on carers
of any cancer, as well as significant emotional and physical challenges.
Methods of development for Clinical Practice Guidelines for the
Management of Adult Gliomas, Astrocytomas and Oligodendroglioma:
The development of these clinical practice guidelines was commenced after a number of consultations
between a wide range of professionals and community personnel who were under considerable
community pressure to address what was considered to be a significant community burden. It had also
been noted from patterns of care surveys (and a formal Victorian studyi) that there were significant
variations in practice around Australia in terms of what was being offered to glioma patients.
Interested clinicians were keen to offer patients around Australia a uniform evidence-based approach
to their management.
This activity was underway but progressing slowly when a generous donation was made to ACN to
promote development of guidelines for managing malignant brain tumours in memory of the donor’s
wife who died from a glioma. The donor requested that a consumer version be developed to
accompany the Guidelines. The patient had a difficult clinical course and had remarked during her
illness that she wished there was a book outlining what standard practice was, as it was so difficult to
know what was best to do at various points in her clinical course.
This same message was frequently reiterated and it was decided to develop a Working Party that
would address the problem and keep an eye on assuring that advice would be given to help people
over serious hurdles.
The first meeting of those interested parties present was rather diffident because of the costs incurred
in developing guidelines to the rigorous requirements as outlined in “A Guide to Development,
Implementation and Evaluation of Clinical Practice Guidelines. NHMRC, Canberra 1999.” The cost of
producing guidelines to this standard were seen to be an expensive matter when the initial group to
promote the development process met in Sydney in March 2005 at the National Glioma Meeting.
Further discussions took place at the COSA Annual Scientific Meeting in Brisbane in 2005 and
decided to proceed without the imprimatur of the NHMRC.
A multidisciplinary representational Working Party was developed with the assistance of the ACN
Secretariat. It was further decided to request the Cancer Council Australia (TCCA) and the Clinical
Oncological Society of Australia (COSA) to undertake accreditation of the Guidelines, once
developed, as it was not appropriate to seek NHMRC endorsement.
Appendices
243
Working party progress
The first meeting of the defined Working Party took place in Sydney on 10 February 2006.
There was again careful consideration addressing finance and urgency before the consensus approach
was chosen.
It was also planned to develop a desktop aide for GPs and a pamphlet for community interest.
A work plan was decided upon to develop Guidelines that would:
•
Assist medical practitioners in their decision making in relation to managing malignant adult
brain tumours.
•
To promote better clinical assessment of malignant adult brain tumours.
•
To provide increased understanding through education of medical carers and the community
of all involved in the care of malignant adult brain tumours.
The Working Party planned to focus on outcomes, through assessing the best available scientific
evidence and this became its activity until completion.
At its initial meeting, topics were decided and chapter leaders chosen. Chapter leaders were charged
to develop teams of contributors to help them progress their chapter.
At a meeting on 22 September 2006, synopses of chapters were presented and showed good progress.
The Working Party Executive met in 2007 to review progress and a decision was taken to have chapter
drafts ready for a review process by 25 December 2007.
Individual chapter reviews were undertaken before a public review process which took place in July
2008.
Following this review, an external review panel met in September 2008 and examined submissions
and made recommendations for the final draft document.
The Executive of the Working Party edited the document in line with the independent reviewers’
recommendations before sending it to TCCA and COSA for approval.
Designation of levels of evidence
I
II
III-1
III-2
III-3
Evidence obtained from a systematic review of all relevant randomised controlled
trials.
Evidence obtained from at least one properly designed randomised controlled trial.
Evidence obtained from well-designed pseudo-randomised controlled trials (alternate
allocation or some other method).
Evidence obtained from comparative studies with concurrent controls and allocation
not randomised (cohort studies), case-control studies, or interrupted time series with a
control group.
Evidence obtained from comparative studies with historical control, two or more
single-arm studies, or interrupted time series without a parallel control group.
In this document all level III has been listed as III regardless of category.
244
Clinical practice guidelines for the management of astrocytoma and oligodendroglioma in adults
IV
Evidence obtained from case series, either post-test or pre-test and post-test.
These levels of evidence ratings have been adapted from US Preventative Service Task Force
(1989), Guide to clinical preventative services: an assessment of the effectiveness of 169
interventions (ed M Fisher), Williams and Williams, Baltimore, Appendix A, p388.
The process of developing the Guidelines was informed by A guide to the development,
implementation and evaluation of clinical practice guidelines, NHMRC Canberra 1999.
Implementation
The level of implementation will depend on budget. It is aimed to have an electronic version posted
for free access on the ACN website, as well as hard copies for those who request it. A Wiki will be
developed to publish and update the guidelines.
It is planned that there will be educational launch activities throughout Australia with major input
from chapter leaders and contributors from around Australia into these launch events. Various
professional and community organisations will be asked to help in this activity.
It is also hoped that the specific recommendations of synoptic reporting for MRIs of brain tumours and
pathology reporting will be taken up by radiologists and pathologists respectively throughout
Australia. There many need to be specific launch activities for these groups.
We aim to encourage the Association of Neurosurgeons to distribute these guidelines to all their
trainees as part of their mandatory training curriculum. Other associated organisations will be
canvassed to assist prior to the final draft.
The newly formed national cooperative trials group for neuro-oncology (known as COGNO) will
specifically be examining the guidelines in terms of where there are gaps in the guidelines and will
aim to develop clinical trial protocols (or to participate in relevant international studies) where
appropriate to address the gaps in our knowledge.
Maintenance
It is envisaged that the guidelines or parts thereof, will be updated where applicable electronically at
regular intervals (eg two-three yearly) only in the areas where there is new high level evidence. We
will retain a Working Party to facilitate these updates and monitor the content of the Wiki.
i
Rosenthal MA, Drummond KJ, Dally M, Murphy M, Cher L, Ashley D, et al. Management of glioma in
Victoria (1998-2000): retrospective cohort study. Med J Aust. 2006 Mar 20; 184(6):270-3.
Appendices
245
Index to Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
abbreviations 240–2
access to treatment 10–11, 212
acetylcholinesterase 220
acupuncture 147
ADC maps see apparent diffusion coefficient (ADC) maps
adjuvant therapy
astrocytomas, high-grade 109–10
astrocytomas, low-grade (LGA) 78–81
adults and tumour types 2–3
age
and incidence rates 2–3
risk factors 4
and survival 92
alternative therapies see complementary and alternative therapies (CAM)
analgesics 31, 217, 226
anti-angiogenic agents 113
anticonvulsant medication 153–6, 198, 217–18
interactions 155–6
propylactic use 152–3
skin reactions 155, 159, 160–1
antidepressants 182
antineoplastic activity 149
antipsychotics 220
anxiety 180–2
aphasia 30
apparent diffusion coefficient (ADC) maps 74, 201
apraxia, dressing 35
astrocytomas 2
determining causes of 4
grade I see astrocytomas, pilocytic
grade II see astrocytomas, diffuse
grade III see astrocytomas, anaplastic
grade IV see glioblastoma multiformes (GBM)
high-grade see astrocytomas, high-grade
low-grade see astrocytomas, low-grade (LGA)
prevention 5
risk factors 4–5
and seizures 34
survival rates 4
tumour types 1, 2
astrocytomas, anaplastic 1, 68–9 see also astrocytomas, high-grade
chemotherapy 110–11, 112–13
radiotherapy 98–9
survival 4
astrocytomas, diffuse 1, 2, 4, 68–9 see also astrocytomas, low-grade (LGA)
astrocytomas, high-grade see also glioblastoma multiformes (GBM)
biopsy 90–2
chemotherapy 92–4, 109–14
computed tomographic scanning (CT) 90
diagnosis 88–9
follow-up 199–201
genetics 89
grading 89
histopathology diagnosis 89
imaging 88–9, 90
key points xviii, 109, 114
prognosis 88
radiotherapy 98–109
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
recommendations xvi–xviii, 90, 92, 94, 95, 96, 97, 98, 99, 100, 102, 106, 107, 108, 109, 110, 111, 112, 113
recurrent 94–5, 112–13
resection of tumours 94–5
risk factors 88
surgery 90–8
survival 4, 51, 88, 103–5
survival and treatment options 90–5, 98–102, 105–14
tissue diagnosis 90
astrocytomas, low-grade (LGA) 45, 46
adjuvant therapy 78–81
brainstem 77
chemotherapy 79–80
diagnosis 73–5
follow-up 201
follow-up imaging 50
image appearances 46
key points xiv–xv, 75, 76, 77, 80
management 75–8
optic pathway/hypothalamic 78
prognosis 80–1
progression to high-grade 201–2
radiotherapy 78–9
sub-types of 77–8
and surgery 49
survival 4, 49, 75
symptoms 30
tectal 77
astrocytomas, pilocytic 1, 2 see also astrocytomas, low-grade (LGA)
ataxia 30
Australian and New Zealand College of Anaesthetists 96
Australian Council on Healthcare Standards 96
Australian Institute of Health and Welfare 2–3
average person years of life lost (AYLL) 1–2
Barthel Index 193
benzodiazepines 218
bereavement 227–8
biopsy 47
astrocytomas, high-grade 90–2
astrocytomas, low-grade (LGA) 75, 76
bladder problems 220–1
blood oxygenation level-dependent (BOLD) functions 52–3
bone effects 158
bowel cancer 36
bowel problems 220–1
brachytherapy 102
Brain Tumour Guidelines Working Party 235–8
brainstem low-grade astrocytomas 77
breaking bad news 12–14, 214–15
cancer 1–2
cancer genetics services 36
carbamazepine (CBZ) 154–6
carboplatin 139, 140
care, continuity of 11
carers
and epilepsy management 153
information provision 14
issues facing 10
and legal aspects 177–9
Index
247
and palliative care 213, 226–7
and psychosocial care 183–4, 185–6
and seizures 173
carmustinge wafers 92–4
case-control studies 5
central nervous system (CNS) cancers 1, 4–5
incidence rates 2–3
central pathological reviews 23
central radiological reviews 24
cerebral blood volume (CBV)
oligodendrogliomas 134
relative 73–4
cerebral hemisphere tumours 3
chemotherapy
adjuvant 109–10
astrocytomas, high-grade 92–4, 109–14
astrocytomas, low-grade (LGA) 79–80
concurrent radiotherapy 110–11
glioblastoma multiformes (GBM) 93
oligodendrogliomas 138–40
children
astrocytomas, low-grade (LGA) 77
information provision 14
needs of 184
and tumour types 2, 3
chromosomes 89–90
1p/19q loss 69–70, 80, 134–5
clinical data 66
clinical presentation 30–6
key points ix, 35, 36
recommendations ix, 32
clinical trials 12, 51
conduct of 22
design of 23–4
endpoints 24–6
ethical reviews 22
importance of 21–2
key points 26
patient participation 22–3
recommendations ix, 26
stratification variables 22–3
types of 21
clonazepam 217
co-operative groups 22
cognitive behavioural therapy 185
cognitive-communication function 194
cognitive function 33–4
assessment of 174–9
changes in 173–4
and clinical trials 25–6
and informed consent 15–16, 23
testing 219–20
and tumour site 219–20
colorectal cancer 36
communication
breaking bad news 12–14, 214–15
difficulty with 173, 194
discussing prognosis 14–17
end of life 225–6
between healthcare professionals 11, 213
248
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
initial consultation 12
treatment options 17–18
community services, palliative care 213–14, 226–7
competence 176–9
complementary and alternative therapies (CAM) 145–9, 180
key points xx, 149
computed tomographic scanning (CT) 41
astrocytomas, high-grade 88–9, 90
astrocytomas, low-grade (LGA) 73
in diagnosis 42–3
and incidence changes over time 3
limitations of 42
oligodendrogliomas 140
post-surgery 49–50
consciousness, loss of 30
consultations 11–16 see also information provision
follow-up 198
continuity of care 213
contrast media 42, 43, 45
Cooperatice Trials Group for Neuro-Oncology (COGNO) 22
corticosteroids 156–7, 216, 217
indications 156, 222
side effects 157, 158, 223
use of 223–4
cost effectiveness of advanced imaging technologies 44, 53
counselling 147
cranial nerve dysfunction 30
cyclizine 218
cytoreduction 91, 95
daily living function ability 194
death
care of dying 223–7
place of 226–7
rates 3
decision making 15–16, 176–9
delirium 182–3
dementia 33–4
depression 180–2, 219–20, 226
dexamethasone 109, 157, 198, 222
diagnosis
astrocytomas, high-grade 88–9
astrocytomas, low-grade (LGA) 73–5
definitive 66
histopathology 45, 66–71, 76, 89
imaging 41–8
and incidence changes over time 3
information provision 12–14
inter-observer variation 69
key points xiv, 71
oligodendrogliomas 134–5
tumour heterogeneity 69
diazepam 217, 218
dietician 191
diffusion imaging 44, 49, 52–3, 201
astrocytomas, high-grade 89, 200
astrocytomas, low-grade (LGA) 73
dizziness 30
driving 18, 153, 194–5, 198
dural enhancement 49–50
Index
249
dysarthria 35
dysembryoplastic neuroepithelial tumours (DNET) 34
dysphagia 218–19
dysphasia 35
educational resources 12, 13, 17
emotional support 15
end of life 178
care of dying 223–7
symptom management 215–23
energy conservation 216, 217
epidemiology 4–5
epilepsy 34–5, 153
anticonvulsant medication 153–6, 159, 160–1, 198, 217–18
surgery for 156
ethical reviews and clinical trials 22
euthanasia 225–6
evidence, levels of 244–5
exercise 192
facial recognition 173
facial weakness 173
familial adenomatous polyposis 36
familial cancer clinics 36
families see also carers
and bereavement 227–8
information provision 14
and palliative care 213
and psychosocial care 183–4
family history
inherited predisposition 35–6
risk factors 4
fatigue 215–16
feeding issues 218–19
FIMTM (Functional Independence Measure) 193
financial matters, patient's 178
fluids at end of life 218–19
fluorescence in situ hybridisation (FISH) 70
fluorodeoxyglucose (18F FDG) 54–5, 134
focal neurological symptoms 30, 33–6
follow-up 198–9
astrocytomas, high-grade 199–201
astrocytomas, low-grade (LGA) 201
imaging 50–2
key points xxiv, 199
oligodendrogliomas 140
frozen sections 12, 66–7
gadolinium enhanced (Gd-MRI) 199, 201
gangliogliomas 34
gastrointestinal side effects 157–8
gender differences 3, 4
general practitioners 11
genetic testing 5, 69
genetics 35–6, 69, 88, 89–90
astrocytomas, high-grade 89
glioblastoma multiformes (GBM) 89–90
hereditary gliomas 36
inherited predisposition 35–6
geographic areas 3
250
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
glial cells 2
glioblastoma multiformes (GBM) 1, 2, 51, 69, 89–90 see also astrocytomas, high-grade
chemotherapy 93, 109, 110, 111, 112–13
genetics 89–90
grading 89–90
image appearances 46
radiotherapy 98–9, 102
resection 92
survival 4, 92
symptoms 30
gliomas see also astrocytomas; oligodendrogliomas
hereditary 36
incidence rates 2
tumour types 1, 2
glossary 239
good practice points, approach to patients viii, 17
grading 68–9
astrocytomas, high-grade 89
glioblastoma multiformes (GBM) 89–90
oligodendrogliomas 69, 134
and survival 4
grief 227–8
group therapy 185
guardianship 178–9
guidelines development process 243–5
hair loss 173
headaches 30–2
treatment of 217
health-related quality of life 25
healthcare professionals see also multidisciplinary teams
co-operative groups 22
communication between 11
discussions with patients 11–18
and legal issues 176–9
providing procedural information 17
second opinions 17
supportive care 17
hemianopia 35
hemiparesis 30, 35
hemiplegia 173
herbal remedies 146, 147–8
hereditary non-polyposis colorectal cancer 36
high-grade glioma (HGG) see astrocytomas, high-grade
histopathology diagnosis 45, 66–71
astrocytomas, high-grade 89
astrocytomas, low-grade (LGA) 76
home care 192, 213, 226–7
homeopathy 148
hope
maintaining 14–15
restoration of 146, 147
hospices 214, 224
hospitals 96–8
and palliative care 213–14
Human Research Ethics Committee (HREC) 22
hydration at end of life 218–19
hydrocephalus 32
imaging see also computed tomographic scanning (CT); magnetic resonance imaging (MRI)
Index
251
advanced and emerging modalities 52–3
aims of 41–2
astrocytomas, high-grade 88–9, 90
and clinical trials 25
considerations 44–6
diagnosis 41–8
diffusion 44, 49, 52–3, 73, 89, 200, 201
follow-up 50–2, 140, 199–202
and headaches 32
intra-operative 48–9, 97–8
key points x–xiv, 42, 44, 46, 47, 48, 49, 50, 52, 53, 55
magnetisation transfer 44
neuroscience centres 41, 44
oligodendrogliomas 134
perfusion 44, 52–3, 73–4, 200, 201
post-surgery 49–50, 199–201
and tumour appearances 46–7
volumetric 44
incidence rates 2–3
information provision 11
astrocytomas, low-grade (LGA) 75
breaking bad news 12–14
and children 184
discussing prognosis 14–17
and feeding issues 218–19
between healthcare professionals 11
initial consultation 12
and psychosocial care 183–4, 185
informed consent
and artificial nutrition 218–19
and cognitive function 15–16, 23
and legal issues 176–9
and tumour banking 70–1
infratentorial tumours 32
integrative medicine 145
intellectual disability 35–6
intensive care units 96
interpreter services 12
intra-operative consultation 66–7
intracranial pressure 30–3
investigator-initiated studies 22
iodinated contrast 42, 43
key points see also recommendations
approach to patients vii–viii, 10, 16
astrocytomas, high-grade xviii, 109, 114
astrocytomas, low-grade (LGA) xiv–xv, 75, 76, 77
clinical presentation ix, 35, 36
clinical trials viii, 26
complementary and alternative therapies (CAM) xx, 149
diagnosis xiv
diagnosis and pathology 71
follow-up xxiv, 199
imaging x–xiv, 42, 44, 46, 47, 48, 49, 50, 52, 53, 55
incidence, causes and prevention vii, 6
low-grade astrocytomas (LGA) 80
oligodendrogliomas xix, 135, 138
palliative care 213, 219, 222, 223, 226, 227, 228
psychosocial care xxii–xxiii, 177, 180, 181, 182, 183, 184
symptoms xxi, 159, 163
252
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
language and discussions with patients 14
legal issues and medical treatment 176–9
leukoencephalopathy 51
Li Fraumeni syndrome 36
limb movements 33
Lisch nodules 35
loss of heterozygosity (LOH) analysis 70
low-grade astrocytomas (LGA) see astrocytomas, low-grade (LGA)
lymphocyte recovery 159
magnetic resonance imaging (MRI) 41
astrocytomas, high-grade 88–9
astrocytomas, low-grade (LGA) 73–4
blood oxygenation level-dependent (BOLD) functions 52–3
contraindications 42–3, 44
in diagnosis 43–4
follow-up imaging 51–2
gadolinium enhanced (Gd-MRI) 199, 201
and incidence changes over time 3
intra-operative imaging 48–9, 97–8
oligodendrogliomas 140
post-surgery 49–50, 199–201
magnetic resonance spectroscopy (MRS) 44, 52–3
follow-up 199–200, 201
oligodendrogliomas 74
magnetisation transfer imaging 44
malignant astrocytic glioma see glioblastoma multiformes (GBM)
malignant transformation 50
mannitol 218, 220
massage 147
Medical Research Council (MRC) prognostic index 103–5
medical treatment and legal issues 176–9
meditation 147
megestrol acetate 216
meningiomas 1, 3, 34
menopause 158
mental health 180–3
methotrimeprazine 218
methylphenidate 220
MGMT (O6-methylguanine-DNA methyltransferase) testing 70
midazolam 217
migraines see headaches
mobile phones 4
mobility aids 192
mortality rates 3
motor/mobility function 192, 194
mouth care 219
multidisciplinary teams 11, 97
and clinical trials 24
and follow-up 198
in neuroscience centres 45
and palliative care 214
and psychosocial care 184
and rehabilitation 191–2, 195
myopathy 192
nausea and vomiting 31, 218
neuro-imaging see imaging
neuro-pathologists 66, 69
Index
253
neurofibromatosis 5, 35, 77–8
neurological performance status 105
neuronavigation 48–9, 97–8
neuropsychological assessment 174
neuropsychological intervention 194
neuroradiologists 45, 96
radiological reports 47–8
neuroscience centres 41, 45, 46
neurosurgeons 45
non-steroidal anti-inflammatory drugs (NSAID) 157–8
nuclear medicine 53–5
nurses 96, 185
nursing homes 213
nutrition 218–19
occupational therapists 191, 192
occupational therapy 195
oedema management 192
cerebral 156–7
oligoastrocytomas (OA) 1, 35, 69, 74
oligodendrogliomas 1, 2, 34, 202
and apparent diffusion coefficient (ADC) maps 74
cerebral blood volume (CBV) 134
chemotherapy 137–40
determining causes of 4
diagnosis 134–5
genetics 35, 69–70
grading 69, 134
high-grade 138–40
image appearances 46
incidence rates 2
key points xix, 135, 138
low-grade 135–8
magnetic resonance spectroscopy (MRS) 74
1p/19q loss (chromosomes) 69–70
prevention 5
recommendations 135, 136, 137
recurrent 141
relative cerebral blood volume (rCBV) 74
risk factors 4–5
and seizures 2
survival 4, 141
oncology nurses 185
1p/19q loss (chromosomes) 69–70, 80, 134–5
operating rooms 96–8
ophthalmoplegia 33
opioids 217, 222
optic gliomas 5
optic nerve gliomas 35
optic pathway/hypothalamic low-grade astrocytomas 78
organic mental disorders 183
osteoporosis 158
pain 217, 222, 226
palliative care 12, 211
bereavement 227–8
breaking bad news 214–15
care of dying 223–7
key points 213, 219, 222, 223, 226, 227, 228
recommendations xxiv–xxvi, 213, 214, 215, 219, 226
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Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
referrals 212, 214
services 211–13
sites of 213–14
standards 211–12
symptom management 215–23, 226
parenchymal damage 49, 50, 54
patho-psysiological changes 52–3
pathologists 66
pathology 66–71
key points 71
oligodendrogliomas 134
pathology reports 66, 67–8
patients
access to treatment 10–11
approach to, key points vii–viii, 10, 16
and clinical trials 22–3
discussing diagnosis 12–14
discussing prognosis 14–15
discussing treatment options 15–16, 17–18
issues facing 10
second opinions 17
treatment decisions 15–16
PCV (procarbazine plus lomustine (CCNU) plus vincristine) 138, 140, 141
peptic ulcers 157–8
perfusion imaging (pMRI) 44, 52–3, 200, 201
astrocytomas, low-grade (LGA) 73–4
permeability magnetic resonance 200, 201
personality changes 173, 183–4
pharmaceutical companies and clinical trials 22
phenobarbitone 218
phenytoin 218
phenytoin (PHT) 154–6
physical changes 173
physiotherapists 191
physiotherapy 195
placebo effect 147
plateau waves 32–3
pneumonia 158
positron emission tomograpgy (PET) 54
astrocytomas, high-grade 200
astrocytomas, low-grade (LGA) 75
oligodendrogliomas 134
post-surgery
imaging 49–50, 199–201
oligodendrogliomas 136
reactive changes 49, 50
posterior tumours 3
power of attorney 178–9
pressure areas 221–2
prevention 5
prognosis
astrocytomas, high-grade 88
astrocytomas, low-grade (LGA) 80–1
discussing 14–17
prognostic systems 103–5
prognostic features 69
progression 24–5
progression-free survival 24–5, 51
propofol 218
proton pump inhibitor 134, 157–8
Index
255
psychological disorders 180–3
psychological treatments 147
psychologists 191
psychosocial care
key points xxii–xxiii, 177, 180, 181, 182, 183, 184
recommendations xxii–xxiii, 174, 176, 177, 179, 181, 183, 184, 186
psychosocial interventions 216, 217
psychosocial issues 173–4
psychostimulants 216–17, 220
psychotherapy, supportive 185
Quality Adjusted Survival Parameters 220
quality of life 25, 147, 179–80, 184
radiation exposure as risk factor 4
radiation necrosis 51, 52, 108–9
Radiation Therapy Oncology Group (RTOG), prognostic systems 103–4
radioactive tracers 54–5
radiological objective responses 25, 51
radiological reports 47–8
radiotherapy
accelerated fractionation 100, 101–2
astrocytomas, high-grade 98–109
astrocytomas, low-grade (LGA) 78–9
brachytherapy 102
concurrent chemotherapy 110–11
delay in initiation 99
dose, optimal 100
fractionation regimens 100–2
hyperfractation 100–1
oligodendrogliomas 136–7
radiation necrosis 51, 52, 108–9
short-course 105–6
skin reactions 160
stereotactic radiosurgery 102
target volumes 106–8
rashes see skin reactions
recommendations see also key points
astrocytomas, high-grade xvi–xviii, 90, 92, 94, 95, 96, 97, 98, 99, 100, 102, 106, 107, 108, 109, 110, 111, 112, 113
clinical presentation ix, 32
clinical trials 26
oligodendrogliomas 135, 136, 137
palliative care xxiv–xxvi, 213, 214, 215, 219, 226
psychosocial care xxii–xxiii, 174, 176, 177, 179, 181, 183, 184, 186
rehabilitation xxiii–xxiv, 192, 195
symptoms xx–xxii, 153, 154, 156, 157, 158, 161, 163, 166, 167
recurrence
astrocytomas, high-grade 94–5, 199–201
oligodendrogliomas 141
referrals
to cancer genetics services 36
to palliative care services 212, 214
for second opinion 17
to specialist care 186
to speech pathologists 192
rehabilitation 191–5
outcome measures 193
programs 219–20
recommendations xxiii–xxiv, 192, 195
relative cerebral blood volume (rCBV) see also cerebral blood volume (CBV)
256
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
astrocytomas, low-grade (LGA) 73–4
and oligodendrogliomas 74
relaxation 147
reports
pathology 67–8
radiological 47–8
research
case-control studies 5
clinical trials 21–6
resection of tumours
astrocytomas, high-grade 90–2, 94–5
astrocytomas, low-grade (LGA) 76–7
degree of resection (DOR) 77
glioblastoma multiformes (GBM) 92
oligodendrogliomas 135
residual tumour 49
respite care 213–14
resuscitation 225–6
risedronate 158
risk factors 4–5
safety requirements for surgery 96–8
scintigraphy 53–5
scoliosis 35
screening 5
second opinions 17
seizures 30, 152 see also epilepsy
and carers 173
end of life 217–18
likelihood of tumour 34–5
prophylactic anti-epileptic drug therapy 152–3
treatment of 217–18
types of 152
self-help organisations 12
sensory changes 173
serum and tumour banking 70–1
shunting 77
single photon emission computed tomography (SPECT) 54, 200–1
skin reactions 158–9
anticonvulsant medication 155, 159, 160–1
drug reactions 159
lymphocyte recovery 159
radiotherapy 160
skin signs 35–6
social workers 191
socio-economic status 3
specimen handling 66
speech deficits 30, 192
speech pathologists 191, 192, 195
speech therapy 192, 194
stereotactic radiosurgery 102
steroids 220, 223–4
support groups 185
supportive care 17
supratentorial tumours 32
surgery
astrocytomas, high-grade 90–8
astrocytomas, low-grade (LGA) 75–6, 77
for epilepsy 156
intra-operative consultation 66–7
Index
257
intra-operative imaging 48–9, 97–8
oligodendrogliomas 135
re-operating 95
safety requirements 96–8
survival 3, 4, 69
astrocytomas, high-grade 4, 51, 88, 90–5, 98–114
astrocytomas, low-grade (LGA) 4, 49, 75
and clinical trials 24
glioblastoma multiformes (GBM) 4, 92
oligodendrogliomas 4, 141
prognostic systems 103–5
swallowing 194
symptoms 30
astrocytomas, high-grade 88
astrocytomas, low-grade (LGA) 73
cognitive function 33–5
end of life 215–23, 226
headaches 30–3
key points xxi, 159, 163
management and complications 152–67
presenting 30
recommendations xx–xxii, 153, 154, 156, 157, 158, 161, 163, 166, 167
seizures 34–5
skin signs 35–6
systematically administered therapies 147–8
tectal low-grade astrocytomas 77
temozolomide 69, 159
astrocytomas, high-grade 106, 110, 111–12, 113–14
oligodendrogliomas 139, 140, 141
thallium (201TI) 54–5, 134
time to progression 24
astrocytomas, low-grade (LGA) 75
tissue
diagnosis 90
removal and handling 66–7
and tumour banking 70–1
touch therapies 147
toxicity 147
tracers, radioactive 54–5
Trans Tasman Radiation Oncology Group (TROG) 22
treatment
access to 10–11
astrocytomas, high-grade 90–114
astrocytomas, low-grade (LGA) 75–8
and carers 153
clinical trials 21–6
discussing options 15–16, 17–18
of headaches 217
and legal issues 176–9
oedema 156–7, 192
oligodendrogliomas 135–40
peptic ulcers 157–8
pressure ulcers 211–12
providing procedural information 17
psychological 147
response to 51
of seizures 217–18
of symptoms 152–67, 215–23, 226
tuberous sclerosis 35–6
258
Clinical practice guidelines for the management of adult gliomas: astrocytomas and oligodendrogliomas
tumour banks 70–1
tumours
cognitive function 33–4
and dementia 33–4
grading 4, 68–9
and headaches 32
heterogeneity 69
and imaging appearances 46–7
locations 34, 180, 219–20
and seizures 34–5
size 51
types 1, 2–3, 4
Turcot syndrome 36
ulcer management
peptic ulcers 157–8
pressure areas 221–2
unproven therapies 145–9
urinary incontinence 33, 220–1
valproic acid (VPA) 154–6
Valsalva manoeuvre 31, 32
venous thromboembolism 162–7
visual disturbances 30, 32–3
volumetric imaging 44
vomiting 31, 218
weakness 173, 191–2
weight gain 173
Wills 178–9
Working Party
membership and contributors 235–8
progress 244
Index
259
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